Note: Descriptions are shown in the official language in which they were submitted.
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NOTE: Pour les tomes additionels, veillez contacter le Bureau Canadien des
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JUMBO APPLICATIONS / PATENTS
THIS SECTION OF THE APPLICATION / PATENT CONTAINS MORE
THAN ONE VOLUME.
THIS IS VOLUME 1 OF 2
NOTE: For additional volumes please contact the Canadian Patent Office.
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1
TRPVI Antogonists And Uses Thereof For The Treatment Of Prevention Of Pain,
UI, And Ulcer, IBD, or HIS In An Animal
I. FIELD OF THE INVENTION
The invention relates to compounds of formula 1, and pharmaceutically
acceptable derivatives thereof, compositions comprising an effective amount of
a
compound of formula I and methods for treating or preventing a condition such
as pain,
Ul, an ulcer, 113D, and IBS, comprising administering to an animal in need
thereof an
effective amount of a compound of formula I.
2. BACKGROUND OF THE INVENTION
Pain is the most common symptom for which patients seek medical advice and
treatment. Pain can be acute or chronic. While acute pain is usually self-
limited,
chronic pain persists for 3 months or longer and can lead to significant
changes in a
patient's personality, lifestyle, functional ability and overall quality of
life (K.M. Foley,
Pain, in Cecil Textbook of Medicine 100-107 (J .C. Bennett and F. Plum eds.,
20th ed.
1996)).
Moreover, chronic pain can be classified as either nociceptive or neuropathic.
Nociceptive pain includes tissue injury-induced pain and inflammatory pain
such as that
associated with arthritis. Neuropathic pain is caused by damage to the
peripheral or
central nervous system and is maintained by aberrant somatosensory processing.
There
is a large body of evidence relating activity at vanilloid receptors (V. Di
lvfarzo et at.,
Current Opinion in Neurobiology 12:372-379 (2002)) to pain processing.
Nociceptive pain has been traditionally managed by administering non-opioid
analgesics, such as acetylsalicylic acid, choline magnesium trisalicylatc,
acetaminophen,
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2
ibuprofen, fenoprofen, diflusinal, and naproxen; or opioid analgesics,
including
morphine, hydromorphone, methadone, levorphanol, fentanyl, oxycodone, and
oxymorphone. Id. In addition to the above-listed treatments, neuropathic pain,
which
can be difficult to treat, has also been treated with anti-epileptics (e.g.,
gabapentin,
UI is uncontrollable urination, generally caused by bladder-detrusor-muscle
instability. UI affects people of all ages and levels of physical health, both
in health care
None of the existing commercial drug treatments for UI has achieved complete
Treatment of ulcers typically involves reducing or inhibiting the aggressive
factors. For example, antacids such as aluminum hydroxide, magnesium
hydroxide,
sodium bicarbonate, and calcium bicarbonate can be used to neutralize stomach
acids.
H, antagonists, such as cimetidine, ranitidine, famotidine, and nizatidine,
are also
used to treat ulcers. 1-12 antagonists promote ulcer healing by reducing
gastric acid and
H+, K+ - ATPase inhibitors such as omeprazole and lansoprazole are also used
to
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Inflammatory-bowel disease ("IBD") is a chronic disorder in which the bowel
becomes inflamed, often causing recurring abdominal cramps and diarrhea. The
two
types of IBD are Crohn's disease and ulcerative colitis.
Crohn's disease, which can include regional enteritis, granulomatous ileitis,
and
ileocolitis, is a chronic inflammation of the intestinal wall. Crohn's disease
occurs
equally in both sexes and is more common in Jews of eastern-European ancestry.
Most
cases of Crohn's disease begin before age 30 and the majority start between
the ages of
14 and 24. The disease typically affects the full thickness of the intestinal
wall.
Generally the disease affects the lowest portion of the small intestine
(ileum) and the
large intestine, but can occur in any part of the digestive tract.
Cramps and diarrhea, side effects associated with Crohn's disease, can be
relieved by anticholinergic drugs, diphenoxylate, loperamide, deodorized opium
tincture, or codeine.
When Crohn's disease causes the intestine to be obstructed or when abscesses
or
fistulas do not heal, surgery can be necessary to remove diseased sections of
the
intestine. Surgery, however, does not cure the disease, and inflammation tends
to recur
where the intestine is rejoined. In almost half of the cases a second
operation is needed.
The Merck Manual of Medical Information 528-530 (R. Berkow ed., 1997).
Ulcerative colitis is a chronic disease in which the large intestine becomes
inflamed and ulcerated, leading to episodes of bloody diarrhea, abdominal
cramps, and
fever. Ulcerative colitis usually begins between ages 15 and 30; however, a
small group
of people have their first attack between ages 50 and 70. Unlike Crohn's
disease,
ulcerative colitis never affects the small intestine and does not affect the
full thickness of
the intestine. The disease usually begins in the rectum and the sigmoid colon
and
eventually spreads partially or completely throughout the large intestine. The
cause of
ulcerative colitis is unknown.
Treatment of ulcerative colitis is directed to controlling inflammation,
reducing
symptoms, and replacing lost fluids and nutrients. Anticholinergic drugs and
low doses
of diphenoxylate or loperamide are administered for treating mild diarrhea.
For more
intense diarrhea higher doses of diphenoxylate or loperamide, or deodorized
opium
tincture or codeine are administered.
Irritable-bowel syndrome ("IBS") is a disorder of motility of the entire
gastrointestinal tract, causing abdominal pain, constipation, and/or diarrhea.
IBS affects
three-times more women than men. In IBS, stimuli such as stress, diet, drugs,
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4
hormones, or irritants can cause the gastrointestinal tract to contract
abnormally. During
an episode of IBS, contractions of the gastrointestinal tract become stronger
and more
frequent, resulting in the rapid transit of food and feces through the small
intestine, often
leading to diarrhea. Cramps result from the strong contractions of the large
intestine and
increased sensitivity of pain receptors in the large intestine.
Treatment of IBS typically involves modification of an IBS-patient's diet.
Often
it is recommended that an IBS patient avoid beans, cabbage, sorbitol, and
fructose. A
low-fat, high-fiber diet can also help some IBS patients. Regular physical
activity can
also help keep the gastrointestinal tract functioning properly. Drugs such as
propantheline that slow the function of the gastrointestinal tract are
generally not
effective for treating IBS. Antidiarrheal drugs, such as diphenoxylate and
loperamide,
help with diarrhea. The Merck Manual of Medical Information 525-526 (R. Berkow
ed.,
1997).
International publication no. WO 98/31677 describes a class of aromatic amines
derived from cyclic amines that are useful as antidepressant drugs.
International publication no. WO 01/027107 describes a class of heterocyclic
compounds that are sodium/proton exchange inhibitors.
International publication no. WO 99/37304 describes substituted
oxoazaheterocycly compounds useful for inhibiting factor Xa.
U.S. Patent No. 6,248,756 to Anthony et al. and international publication no.
WO 97/38665 describe a class of piperidine-containing compounds that inhibit
farnesyl-
protein transferase (Ftase).
International publication no. WO 98/31669 describes a class of aromatic amines
derived from cyclic amines useful as antidepressant drugs.
International publication no. WO 97/28140 describes a class of piperidines
derived from 1-(piperazin-1-yl)aryl(oxy/amino)carbony1-4-aryl-piperidine that
are useful
as 5-HT! Db receptor antagonists.
International publication no. WO 97/38665 describes a class of piperidine
containing compounds that are useful as inhibitors of farnesyl-protein
transferase.
U.S. Patent No. 4,797,419 to Moos etal. describes a class of urea compounds
for
stimulating the release of acetylcholine and useful for treating symptoms of
senile
cognitive decline.
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U.S. Patent No. 5,891,889 describes a class of substituted piperidine
compounds
that are useful as inhibitors of farnesyl-protein transferase, and the
farnesylation of the
oncogene protein Ras.
U.S. Patent No. 6,150,129 to Cook etal. describes a class of dinitrogen
5 heterocycles useful as antibiotics.
U.S. Patent No. 5,529,998 to Habich et al. describes a class of benzooxazolyl-
and benzothiazolyloxazolidones useful as antibacterials.
International publication no. WO 01/57008 describes a class of 2-
benzothiazoly1
urea derivatives useful as inhibitors of serine/threonine and tyrosine
kinases.
International publication no. WO 02/08221 describes aryl piperazine compounds
useful for treating chronic and acute pain conditions, itch, and urinary
incontinence.
International publication no. WO 00/59510 describes aminopyrimidines useful as
sorbitol dehydrogenase inhibitors.
Japanese patent application no. 11-199573 to Kiyoshi etal. describes
benzothiazole derivatives that are neuronal 5HT3 receptor agonists in the
intestinal canal
nervous system and useful for treating digestive disorders and pancreatic
insufficiency.
German patent application no 199 34 799 to Rainer et al. describes a chiral-
smectic liquid crystal mixture containing compounds with 2 linked
(hetero)aromatic
rings or compounds with 3 linked (hetero)aromatic rings.
M. Chu-Moyer et al., J. Med. Chem. 45:511-528 (2002) describes heterocycle-
substituted piperazino-pyrimidines useful as sorbitol dehydrogenase
inhibitors.
B.G. Khadse etal., Bull. Half Instt. 1(3):27-32 (1975) describes 2-(N4-
substituted-NI-piperazinyl) pyrido(3,2-d)thiazoles and 5-nitro-2-(N4-substit-
uted-
N/-piperazinyl)benzthiazoles useful as anthelmintic agents.
U.S. Patent Application Publication No. US 2004/0186111 Al and International
publication no. WO 2004/058754 Al describe a class of compounds that are
useful for
treating pain.
U.S. Patent Application Publication No. US 2006/0199824-Al and International
publication no. WO 2005/009987 Al describe a class of compounds that are
useful for
treating pain.
U.S. Patent Application Publication No. US 2006/0128717 Al and International
publication no. WO 2005/009988 Al describe a class of compounds that are
useful for
treating pain.
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6
There remains, however, a clear need in the art for new drugs useful for
treating
or preventing pain, UI, an ulcer, IBD, and IBS. Citation of any reference in
Section 2 of
this application is not to be construed as an admission that such reference is
prior art to
the present application.
3. SUMMARY OF THE INVENTION
The invention encompasses compounds of formula I:
Ar1R4
(R3)m
N/
R2
XNr0
Ar2
(I)
or a pharmaceutically acceptable derivative thereof, where
X is 0, S, N-CN, N-OH, or N-0R10;
W is N or C;
the dashed line denotes the presence or absence of a bond, and when the dashed
line denotes the presence of a bond or W is N then R4 is absent, otherwise R4
is -H, -OH,
-0CF3, -halo, -(Ci-C6)alkyl, -CH2OH, -CH2C1, -CH2Br, -CH2I, -CH2F, -CH(halo)2,
-CF3, -0R10, -
COOH, -COORio, -C(0)R10, -C(0)H, -0C(0)R10, -0C(0)NFIR10,
-NHC(0)R13, -CON(R13)2, -S(0)2R10, or -NO2;
R10 is -(C1-C4)alkyl;
each R13 is independently -H, -(C1-C4)alkyl, -(C1-C4)alkenyl, -(C1-C4)alkynyl,
or
¨phenyl;
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Ari is
(R2)n (R2)n (R2)n N (R2)n
N ,,,\ N ' ';
1 I
RiN , ,
Ri ' Ri , Ri
¨,õ,õõ,,, VIANINW \ WVVVVVVN
(R2)p ,N (R2)p. (R2)p
11 N =\' N N'\
1
N/-.,-. , /1,) ' )N
Ri rs1 R1
VVIAAAAM VVVVVVVV,
VS/VV./NAM
N,N (R2)p .N.... (R2)p
'
To-c2)p II
)) , or
Ri Ri RiN
vv,,,,,,, VVVVVVVV, VVVVWVNIN
Ar2 is
JNAnn
''SrVVµ
N' N¨R20 I\V s N' 0
i
y2 R12a
V3)c
R8 R9 R8 R9 R8 R12b
R9
I ¨(R14)1 I ¨(R14)
, 1
Y2 rt
Y .
1 y
, 1
\( Y3)C E (Y3)C v
vv.
v:\l^
or
N\9 . \=A
(R14)q (R14 N (R14)q (R14)s (R11)r .
,
C is the integer 0, 1, or 2;
Yi, Y2, Y3 are independently C, N, or 0;
wherein no more than one of Y1, Y2, or Y3 can be 0, and for each Y1, Y2, and
Y3
that is N, the N is bonded to one R21 group, and for each Yi, Y2, and Y3 that
is C, the C is
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8
bonded to two R20 groups, provided that there are no more than a total of two
(C1-
C6)alkyl groups substituted on all of Y1, Y2, and Y3;
RI2a and R12b are independently -H or -(C1-C6)alkyl;
E is =0, =S, =CH(CI-05)alkyl, =CH(CI-05)alkenyl, -NH(C1-C6)alkyl, or =N-
S OR2o;
R1 is -H, -halo, -(C1-C4)alkyl, -NO2, -CN, -OH, -OCH3, -NH2, -C(halo)3,
-CH(halo)2, -CH2(halo), -0C(halo)3, -OCH(halo)2, or -OCH2(halo);
each R2 is independently:
(a) -halo, -OH, -0(CI-C4)alkyl, -CN, -NO2, -NH2, -(C1-C o)alkyl, -(C2-
Cio)alkenyl, -(C2-C10)alkynyl, -phenyl, or
(b) a group of formula Q;
wherein Q is
0
Z3 Z3 Z1 Z3Z4 Z1>Az 0-Z3
4
, Z2 Z3
../V1A"
SAINIV.IVVV%
0
R20
HN,R20
Zz
33 I
..., Z3
4 Z3 c_3 ' Z3
H, vw
0 0
LI V
N R20 C)NR20
N R20
Z2 Zwvuw'3 , Z2 Z3 or zo
Z3
=
Z1 is -H, -0R7, -SR7, -CH2-0R7, -CH2-SR7, -CH2-N(R20)2, or -halo;
Z2 is -H, -(C1-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, -CH2-0R7, -phenyl,
or
-halo;
each Z3 is independently -H, -(C1-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl,
or
-phenyl;
Z4 is -H, -OH, -ORD), -(Ci-C6)alkyl, or -N(R20)2;
J is -0R20, -SR20, -N(R20)2, or -CN;
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provided that at least one R2 group is a group of formula Q, and provided that
when Z1 is -0R7 or -SR7, then Z2 is not -halo;
each R3 is independently:
(a) -H, CH2OR7, or (C1-C6)alkyl; or
(b) two R3 groups together form a (C7-C6)bridge, which is unsubstituted
or substituted with 1, 2 or 3 independently selected R8 groups, and which
bridge
optionally contains -HC=CH- within the (C2-C6)bridge; or
(c) two R3 groups together form a -CH2-N(R0)-CH2- bridge, a
Rb Rb
co
0- S-0
CH2-N-CH2- bridge, or a -CH2-N-CH2- bridge;
R, is selected from -H, -(Ci-C6)alkyl, -(C3-C8)cycloalkyl, -CH2-C(0)-R,
-(CH2)-C(0)-OR, -(CH2)-C(0)-N(Rc)2, -(C142)2-0-Rc, -(CF12)2-S(0)2-N(R)2, or
-(CH2)2-N(R)S(0)2-Re;
Rb is selected from:
(a) -H, -(C1-C6)alkyl, -(C3-C8)eycloalkyl, -(3- to 7-
membered)heterocycle, -N(R)2, -N(Rc)-(C3-C8)cycloalkyl, or -N(Re)-(3- to 7-
membered)heterocycle; or
(b) -phenyl, -(5- or 6-membered)heteroaryl, -N(R)-phenyl, or -N(Re)-(5-
to 10-membered)heteroaryl, each of which is unsubstituted or substituted with
1, 2 or 3
independently selected R7 groups;
each Rc is independently selected from -H or -(C1-C4)alkyl;
each R7 is independently -H, -(C1-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl,
-(C3-C8)cycloalkyl, -(C5-C8)cycloalkenyl, -phenyl, -(Ci-C6)haloalkyl, -(C1-
C6)hydroxyalkyl, -(C1-C6)alkoxy(CI-C6)alkyl, -(C1-C6)alkyl-N(R20)2, or -
CON(R20)2;
each R8 and R9 is independently
(a) -(C1-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, -(C3-C8)cycloalkyl, -
(C5-C8)cycloalkenyl, or -phenyl, each of which is unsubstituted or substituted
with 1 or
2 -OH groups; or
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(b) -H, -CH2C(halo)3, -C(halo)3, -CH(halo)2, -CH2(halo), -0C(halo)3,
-OCH(halo)2, -OCH2(halo), -SC(halo)3, -SCH(halo)2, -SCH2(halo), -CN, -0-CN, -
OH,
-halo, -N3, -NO2, -CH=NR7, -N(R7)2, -NR7OH, -0R7, -C(0)R7, -C(0)0R7, -0C(0)R7,
-0C(0)0R7, -SR7, -S(0)R7, or
5 each Rli is independently -CN, -OH, -(CI-C6)alkyl, -(C2-C6)alkenyl, -
halo, -N3,
-NO2, -N(R7)2, -CH=NR7, -NR7OH, -0R7, -C(0)R7, -C(0)0R7, -0C(0)R7, or
-0C(0)0R7;
each R14 is independently -H, -(Ci-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl,
-
(C3-C8)cycloalkyl, -(C5-C8)cycloalkenyl, -(C -C6)alkoxy-(C -C6)alkyl, -phenyl,
10 -C(halo)3, -CH(halo)2, -CH2(halo), -(3- to 7-membered)heterocycle, -(C1-
C6)haloalkyl,
-(C2-C6)haloalkenyl, -(C2-C6)haloalkynyl, -(C2-C6)hydroxyalkenyl, -(C2-
C6)hydroxyalkynyl, -(C1-C6)alkoxy(C2-C6)alkyl, -(C1-C6)alkoxy(C2-C6)alkenyl, -
(CI-
C6)alkoxy(C2-C6)alkynyl, -(CI-C6)alkoxy(C3-C8)cycloalkyl,-CN, -OH, -halo,
-0C(halo)3, -N3, -NO2, -CH=NR7, -N(R7)2, -NR7OH, -0R7, -SR7, -0(CH2)b0R7, -
0(CH2)bSR7, -0(CH2)bN(R7)2, -N(R7)(CH2)b0R7, -N(R7)(CH2)bSR7,
-N(R7)(CH2)bN(R7)2, -N(R7)COR7, -C(0)R7, -C(0)0R7, -0C(0)R7, -0C(0)0R7,
-S(0)R7, or -S(0)2R7, -S(0)2N(R7)2, -S02C(halo)3, S02(3-to 7-
membered)heterocycle,
-CON(R7)2, -(C1-05)alkyl-C=NOR7, -(CI -05)alkyl-C(0)-N(R7)2, -(CI-C6)alkyl-
NHSO2N(R7)2, or -(C1-C6)alkyl-C(=NH)-N(R7)2;
each R20 is independently -H, -(C1-C6)alkyl, or (C3-C8)cycloalkyl;
each R21 is independently -H, -(C1-C6)alkyl,
,
or
each halo is independently -F, -Cl, -Br, or -I;
n is the integer 1,2, or 3;
p is the integer 1 or 2
each b is independently the integer 1 or 2;
q is the integer 0, 1, 2, 3, or 4;
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r is the integer 0, 1, 2, 3, 4, 5, or 6;
s is the integer 0, 1, 2, 3, 4, or 5;
t is the integer 0, 1, 2, or 3; and
m is the integer 0, 1, or 2.
Compounds of formula I are potent at TRPV1 receptors, and are highly soluble
in aqueous solutions at either pH 6.8 or pH 1.2.
A compound of formula I, or a pharmaceutically acceptable derivative thereof,
is
useful for treating or preventing pain, Ul, an ulcer, IBD, or IBS (each being
a
"Condition") in an animal.
The invention also relates to compositions comprising an effective amount of a
compound of formula I, or a pharmaceutically acceptable derivative thereof,
and a
pharmaceutically acceptable carrier or excipient. The compositions are useful
for
treating or preventing a Condition in an animal.
The invention further relates to methods for treating a Condition comprising
administering to an animal in need thereof an effective amount of a compound
of
formula I, or a pharmaceutically acceptable derivative thereof.
The invention further relates to use of a compound of formula I in the
manufacture of a medicament for treating and/or preventing a Condition.
The invention further relates to methods for preventing a Condition comprising
administering to an animal in need thereof an effective 'amount of a compound
of
formula I, or a pharmaceutically acceptable derivative thereof.
The invention still further relates to methods for inhibiting Transient
Receptor
Potential Vanilloid 1 ("TRPV1," formerly known as Vanilloid Receptor 1 or VR1)
function in a cell, comprising contacting a cell capable of expressing TRPV1
with an
effective amount of a compound of formula I, or a pharmaceutically acceptable
derivative thereof.
The invention still further relates to a method for preparing a composition
comprising the step of admixing a compound of formula I, or a pharmaceutically
acceptable derivative thereof, and a pharmaceutically acceptable carrier or
excipient.
The invention still further relates to a kit comprising a container containing
an
effective amount of a compound of formula I, or a pharmaceutically acceptable
derivative thereof.
Preferred compounds of formula I are compounds of formula II:
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AriõR4
21 (R3)
X R20
l\r
Ar2
(II)
or a pharmaceutically acceptable derivative thereof, where the dashed line, W,
X, Ark
Ar7, R3, R4, R20, and m are as defined above for compounds of formula I,
wherein Q is
Zi)717z3
Z2 Z3
Zi is -OH, -SH, -N(R0)2, -CH2-0H, -CH,-SH, or -CH2-N(R202;
Z2 is ¨H, -CH3, or -CH2-0R7;
each Z3 is independently ¨H or ¨CH3; and
J is -OH, -SH, or -N(R20)7.
Compounds of formula II are highly soluble in aqueous solutions at either pH
6.8
or pH1.2, are very potent at the TRPV I receptor, have good bioavailability,
and have a
good therapeutic index.
Preferred compounds of formula II are compounds of formula III:
Ari. .R4
/0.,
l"3/m
,
X NH
Ar2
(III)
or a pharmaceutically acceptable derivative thereof, where the dashed line, W,
X, Ari,
Ar2, R3, R4, and m are as defined above for compounds of formula I,
wherein An is:
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HO
OH
I
Ri N
R1 is ¨Cl, -F, or ¨CF3;
wherein Ar2 is:
.A.n./NA JNAAA
JVV, Js.rtn,
401 401
NNS
CF3 R14'4111 D "14'
R14 R14' , CF 0\ F3CS0
2 CF3 Or
CF3
R8 R9
R14 is ¨H, -Cl, -F, -Br, -0CF3, -(Ci-C6)alkyl, -S02CF3, -S02(Ci-C6)alkyl,
-OCH3, -OCH2CH3, or -OCH(CH3)2, and preferably is -CF3, -0CF3, -Cl, or ¨F;
R14, is ¨H, -F, -Br, -CH3, -Cl2CH3, -
OCH3, -0CF3, or ¨OCH2CH3; and
each R8 and R9 is independently -H, -Cl, -Br, -F, -CH3, -OCH3, -OCH2CH3,
-CF3, -0CF3, iso-propyl, or tert-butyl.
Compounds of formula III are highly soluble in aqueous solutions at either pH
6.8 or pH 1.2, are exceptionally potent at TRPV1 receptors, have excellent
bioavailability, have a high therapeutic index, and are believed to be highly
efficacious
in animals for the treatment of pain.
The invention can be understood more fully by reference to the following
detailed description and illustrative examples, which are intended to
exemplify non-
limiting embodiments of the invention.
4. BRIEF DESCRIPTION OF THE FIGURES
Fig 1. 96-well plate with different agonist solutions (Agonist Plate). Seven
different sulfuric acid solutions, or agonist solutions, with different
sulfuric acid
(H2SO4) concentrations (of from 15.0 mM to 18 mM as indicated) were used for
the pH
assay as indicated. For the wells in row A, measuring buffer alone was used.
The final
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14
concentration of sulfuric acid in the wells for each row, after a 1:4 dilution
of the agonist
solution, is also indicated in each row in parenthesis.
Fig 2. pH dependent Ca2+ responses in TRPV1/CHO cells. Ca2+ influx into
TRPV1/CHO cells as measured by Fura-2 AM fluorescence is indicated by the
graph
within each rectangular field. The graph presents the fluorescence intensity
over time
starting from the addition of agonist solution. Each rectangular field
presents one
experiment performed in one well of a 96-well plate. Each row presents six
experiments
performed at the same final sulfuric acid concentration; the final sulfuric
acid
concentration is indicated at the left. Actual pH values were measured after
the
experiment and are indicated above the graph. No antagonists were added to the
cell
culture. Final sulfuric acid concentrations of 3.2 and 3.3 mM produced an
appropriate
Ca response and were selected for subsequent assays. These final
sulfuric acid
concentrations can be obtained by 1:4 dilutions of agonist solution with
sulfuric acid
concentrations of 16.0 mM or 16.5 mM, respectively (see Fig. 1).
Fig 3. (A) A 96-well plate with two different sulfuric acid concentrations.
Wells
in columns 1 to 6 had one final sulfuric acid concentration; wells in columns
7 to 12 had
a different final sulfuric acid concentration. The final sulfuric acid
concentration was
reached by 1:4 dilution of two different agonist solutions with sulfuric acid
concentrations of X mM and (X + 0.5) mM, respectively. In the experiment
described in
Section 2 of Protocol 2, X was determined to be 16 mM. (B) A 96-well plate
with
different test compound, or antagonist, concentrations indicated in nM. Only
one kind
of test compound was applied per 96-well plate. Since two different sulfuric
acid
concentrations were used (columns 1-6 vs. columns 7-12), seven wells were
tested for
each combination of test compound concentration and agonist solution (e.g.,
wells Al,
B1, Cl, El, Fl, GI, and HI were tested for test compound concentration 0.977
nM and
agonist solution with sulfuric acid solution X mM). The wells in row D did not
include
an antagonist in order to measure the maximal Ca2+ response.
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5. DETAILED DESCRIPTION OF THE INVENTION
5.1 COMPOUNDS OF FORMULA I
5
The invention encompasses compounds of formula I:
Ari. ,R4
-(R3)m
R20
Ar2
(I)
or a pharmaceutically acceptable derivative thereof, where W, X, Ari, Ar-,,
R3, R4, R10,
and m are as defined above for compounds of formula I.
Certain embodiments of formula I are presented below.
In one embodiment, a compound of formula I is a pharmaceutically acceptable
derivative of a compound of formula I.
In another embodiment, a compound of formula I is a compound of formula I
whererein the derivative is a pharmaceutically acceptable salt.
In another embodiment, a compound of formula I is a pharmaceutically
acceptable salt of a compound of formula I.
In another embodiment, Ari is a pyridyl group.
In another embodiment, Art is a pyrimidinyl group.
In another embodiment, Ari is a pyrazinyl group.
In another embodiment, An is pyridazinyl group.
In another embodiment, W is C.
75 In another embodiment, W is N.
In another embodiment, X is 0.
In another embodiment, X is S.
In another embodiment, X is N-CN.
In another embodiment, X is N-OH.
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In another embodiment, X is N-ORIo.
In another embodiment, Ar2 is a benzoimidazolyl group.
In another embodiment, An is a benzothiazolyl group.
In another embodiment, Ar2 is a benzooxazolyl group.
In another embodiment, Ar2 is
I
(Rizt)ci
In another embodiment, Ar2 is
(R14)q
In another embodiment, An is
15vvwrn
(R14)s
In another embodiment, Ar2 is
(R14 )q
=
In another embodiment, An) is
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\K
(R11)r .
In another embodiment, Ai,' is
¨
S N/R21
'
In another embodiment, Ar, is
¨
Si
N,
R21.
In another embodiment, Ar2 is
JNAArt
So
=
In another embodiment, n or p is 1.
In another embodiment, n or p is 2.
In another embodiment, n is 3.
In another embodiment, m is 2.
In another embodiment, each R3 is independently ¨H, or (Ci-C6)alkyl.
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In another embodiment, two R3 groups together form a (C2-C6)bridge, which is
unsubstituted or substituted with 1, 2 or 3 independently selected Rg groups,
and which
bridge optionally contains -HC=CH- within the (C2-C6)bridge.
In another embodiment, two R3 groups together form a (C2-C6)bridge, which is
unsubstituted or substituted with an Rg group, and which bridge optionally
contains
-HC=CH- within the (C2-C6)bridge.
In another embodiment, two R3 groups together form a (C2-C3)bridge, which is
unsubstituted or substituted with an Rg group, and which bridge optionally
contains
-HC=CH- within the (C2-C3)bridge.
In another embodiment, two R3 groups together form a (C2-C3)bridge, which is
unsubstituted and which bridge optionally contains -HC=CH- within the (C2-
C3)bridge.
In another embodiment, two R3 groups together form a (C2)bridge, a -HC=CH-
bridge, or a (C3)bridge each of which is unsubstituted.
In another embodiment, two R3 groups together form a (G2-C6)bridge, which is
unsubstituted or substituied with 1, 2 or 3 independently selected Rg groups,
which
bridge optionally contains -HC=CH- within the (C2-C6)bridge, and which bridge
joins
positions 2 and 6 of the piperidine, 1,2,3,6-tetrahydropyridine or piperazine
ring.
In another embodiment, two R3 groups together form a (C2-C6)bridge, which is
unsubstituted or substituted with an Rg group, which bridge optionally
contains
-HC=CH- within the (C2-C6)bridge, and which bridge joins positions 2 and 6 of
the
piperidine, 1,2,3,6-tetrahydropyridine or piperazine ring.
In another embodiment, two R3 groups together form a (C2-C3)bridge, which is
unsubstituted or substituted with an Rg group, which bridge optionally
contains
-HC=CH- within the (C2-C3)bridge, and which bridge joins positions 2 and 6 of
the
piperidine, 1,2,3,6-tetrahydropyridine or piperazine ring.
In another embodiment, two R3 groups together form a (C2-C3)bridge, which is
unsubstituted, which bridge optionally contains -HC=CH- within the (C2-
C3)bridge, and
which bridge joins positions 2 and 6 of the piperidine, 1,2,3,6-
tetrahydropyridine or
piperazine ring.
In another embodiment, two R3 groups together form a (C2)bridge, a -HC=CH-
bridge, or a (C3)bridge each of which is unsubstituted, and which bridge joins
positions
2 and 6 of the piperidine, 1,2,3,6-tetrahydropyridine or piperazine ring.
In another embodiment, two R3 groups together form a -CH2-N(Ra)-CH2- bridge
(B1), a
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Rb Rb
C == 0 0 S 0
¨ CH2 -N-CH2 - bridge (B2), or a -CH2 -N-CH2 - bridge (B3);
wherein Ra is selected from -H, -(CI-C6)alkyl, -(C3-C8)cycloalkyl, -CH2-C(0)-
R,, -(CH2)-C(0)-OR, -(CH2)-C(0)-N(Rc)2, -(CH2)2-0-R, -(CH2)2-S(0)2-N(Rc)2, or
-(CH2)2-N(Rc)S(0)2-R;
Rh is selected from:
(a) -H, -(Ci-C6)alkyl, -(C3-C8)cycloalkyl, -(3- to 7-
membered)heterocycle, -N(R)2, -N(Rc)-(C3-C8)cyc1oalkyl, or -N(Re)-(3- to 7-
membered)heterocycle; or
(b) ¨phenyl, -(5- or 6-membered)heteroaryl, -N(R)-phenyl, or
to 10-membered)heteroaryl, each of which is unsubstituted or substituted with
1, 2 or 3
independently selected R7 groups; and
each Rc is independently selected from -H or -(C1-C4)alkyl;
In another embodiment, the BI, B2, or B3 bridge joins positions 2 and 6 of the
piperidine, 1,2,3,6-tetrahydropyridine or piperazine ring.
In another embodiment, two R3 groups form a bicyclo group to give one of the
following structures,
,R4 Ari. R4
(N) orN)
R R20
Nr20 Xl\r
Ar2 Ar2
In another embodiment, m is 1.
In another embodiment, m is 0.
In another embodiment, s or q is 0.
In another embodiment, s or q is 1.
In another embodiment, s or q is 2.
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In another embodiment, R1 is -H.
In another embodiment, R1 is -halo.
In another embodiment, R1 is -Cl.
In another embodiment, R1 is -F.
5 In another embodiment, R1 is -CH3.
In another embodiment, R1 is -NO2.
In another embodiment, R1 is -CN.
In another embodiment, R is -OH.
In another embodiment, R1 is -OCH3.
10 In another embodiment, R1 is -NH2.
In another embodiment, R1 is -C(halo)3.
In another embodiment, R1 is ¨CF3.
In another embodiment, R1 is -CH(halo)2.
In another embodiment, R1 is -CH2(halo).
15 In another embodiment, Art is a pyridyl group and n is 1.
In another embodiment, Ari is a pyrazinyl group and p is 1.
In another embodiment, An is a pyrimidinyl group and p is 1.
In another embodiment, Ari is a pyridazinyl group and p is 1.
In another embodiment, when n and p are 1, then R2 must be Q.
20 In another embodiment, Q is
Z3 Z¨z3 c) Z4 Ori\¨ Z3
\/
vwvvvvv.
Oy R20
R20 0 I I R
Z3
NH
Z3 0 , Z3
rvvvtivvvv=
I/O
N
HõS, R20 R20 N R20
j\¨ Z3
Z2 Z3 , Z2 Z3 or z2 Z3
vvvvw,""
In another embodiment, Q is
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J 0 J 0
J7 xi-L.2(J
Z3 Z3 Zy\-- Z3 Z4 Z1>)L Z4
Z3 i
, Z2 z3, , Z2 4 Z2 Z3 Z3
or vs..
In another embodiment, Q is
J J
J Z1,7Z 0Z3
Z3......,_.õ.. Z3 3 0,z4 ....,,
, Z1 Z3,
or Z3
.
In another embodiment, Q is
J
J
1.....i>71\ ¨7
Z3...õ.....õ.. Z3 c_3
or Z2 Z3
In another embodiment, Q is
J
-I'
O4 0,...,k Z3
Z3
or
In another embodiment, Q is
,-
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0 j 0
0.,,, Z4 Zl>/L --, 0,¨ Z3 Z>)1)( si
4 7
, Z2 Z2 Z3 Z3
,
vvvv.vvv. wys= .,,,,,,A v.v.,. vvvs.,vvv,
5
0 0
0
0- -1-=ji ... Hõ
20 N R20 S, 0 R20
----S--
Z 1...- Z3 ZNH
5
Z3---).-- Z2 Z3 , Z3
pp
0 H
H,
HIV NA R20 I
0,N
R20 R 20
Z.3__\A., Z>______-\-- Z3
Zi>____.--\-- Z3
Z3 0 5 Z2 Z3 or Z2 Z3
In another embodiment, Q is
J
0.71\¨ Z3
Z3
MANIANV, ' VIM/WWI
0 0/P
0---11 R H,
20 N R20 0 R20
----S---
Z3 I Z
NH 5 Zi.õ\_____s--Z3 3 NH
Z3 Z2 Z3 , Z3
5
,0 H
H, I
R
HI\ 20 Nr R20 OR 20
Z.3....õ...\ As Z.>_____4- Z3
Zi>õ,---7 Z3
Z3 0 , Z2 Z3 or Z2 Z3
5 wVVVW
In another embodiment, Q is
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0 0 0
u o//,,
0---11 R ii,N,,, R20
I -----S--- 20 O R20
Z3 H Zi.>___s--Z3
Zr'--- Z2
, Z3 , Z3 ,
s.,,,,.,..".
0 H
H,A I
R20 0 NR20
HN N R20
Zz3
Z1>__._.¨\¨ Z3
Z3 0 , 4 Z3 or Z2 Z3
In another embodiment, Q is
_
0
0\/,O
,_,
0..... ji R I 1.,N,. R20
----S---- 20
Z3 H Z
Z\-- 3
Z3"---1--- Z2
or Z3
=
In another embodiment, Q is
0 H
HA. I
Oy R20
HN R20 0 N R20
Z.3_,Y¨ Z>___1\¨z3
Zi>-\-- Z3
Z3 , Z3 0 , 4 Z3 or Z2 Z3
In another embodiment, Q is
J
Z3...........,õ 4
In another embodiment, Q is
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Z2 Z3
In another embodiment, Q is
.,/Z4
In another embodiment, Q is
0
Zi>)-LZ4
Z2
In another embodiment, Q is
0¨Z3
Z3
In another embodiment, Q is
0
Zi>)-)(
Z2 Z3 Z3
In another embodiment, J is -ORR', -SR20 or -N(R20)2.
In another embodiment, J is ¨0R20.
In another embodiment, J is ¨OH.
In another embodiment, J is ¨CN.
In another embodiment, Z1 is ¨H.
In another embodiment, Z1 is ¨OH.
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In another embodiment, Zi is ¨OCH3.
In another embodiment, Z1 is ¨CH2OH.
In another embodiment, Z2 is -CH2-0R2.
In another embodiment, Z2 is -CH2OH.
5 In another embodiment, Z2 is -H, -(C1-C6)alkyl, -(C2-C6)alkenyl,
C6)alkynyl, -phenyl, or ¨halo.
In another embodiment, Z2 is ¨H.
In another embodiment, Z2 is ¨CH3.
In another embodiment, Z3 is ¨H.
10 In another embodiment, Z3 is ¨CH3.
In another embodiment, Z4 is ¨H.
In another embodiment, Z4 is -(C1-C6)alkyl.
In another embodiment, Z4 is -N(R20)2.
In another embodiment Z4 is ¨0R20.
15 In another embodiment, Z4 is ¨OH.
In another embodiment, Q is
OH OH \.OH NH
2
0
====..õ,
, ,
OH OH OH OH OH OH
HO,õ.) HOJ HO
,
VWV`JVINN VVVV.MA WWWW
A
OH OH OH OH
F>) HO,õ.)
vvflnnAn
OH
VVVVVVVV,
VVWVNAM ~AMNIA
0 0 0=S= 0
C) AOH )(40/
- or NH
, , =
20 In another embodiment, Q is
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I
OH OH OH NH2
, or
=
In another embodiment, Q is
OH OH OH OH OH OH
HO,,,. H0) HO HOo,;,.)
N
OH OH OH OH
F>) HO,õ.) )
or OH
F
.
In another embodiment, Q is
OH OH OH OH OH
OH OH OH
HO,õ.) HO,.) HO HO,
'
or OH
vvvvvvvv, vvvvi..nnr,
vv.VUVUV'.A .
In another embodiment, Q is
OH OH OH OH OH OH
Haõ,) HO.,..) HO HO)
0, or
,
' vsn.rvtn.n.nn ,,,,, .
In another embodiment, Q is
OH OH OH OH
HO,õ.) H0) HO..) HO?)
or
, .
In another embodiment, Q is
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0 0
00H ()0 OO
)LOH
vv., , vvvvvvvv, vvvvvvvv, wwww, or
In another embodiment, Q is
0=S=0
NH
In another embodiment, m is 1 and R3 is -(Ci-C6)alkyl.
In another embodiment, m is I and R3 is -CH3.
In another embodiment, m is 0.
In another embodiment, R4 is -OH.
In another embodiment, R4 IS -0CF3
In another embodiment, R4 is -halo.
In another embodiment, R4 is -F.
In another embodiment, R4 is -Cl.
In another embodiment, R4 is -(CI-C6)alkyl.
In another embodiment, R4 IS -CH3.
In another embodiment, R4 is -CH,OH.
In another embodiment, R4 is -CH2C1.
In another embodiment, R4 is -CH2Br.
In another embodiment, R4 IS -CH2I.
In another embodiment, R4 is -CH2F.
In another embodiment, R4 is -CH(halo)2.
In another embodiment, R4 is -CF3.
In another embodiment, R4 is -NO2.
In another embodiment, R4 is -ORIO.
In another embodiment, R4 is -SRIO.
In another embodiment, R4 IS -C(0)R10.
In another embodiment, R4 is -COOH.
In another embodiment, R4 is -C(0)H.
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In another embodiment, R4 is -COORIO.
In another embodiment, R4 is -0C(0)R10.
In another embodiment, R4 is -S02R10.
In another embodiment, R4 is -0C(0)NFIR10=
In another embodiment, R4 is -NHC(0)R13.
In another embodiment, R4 is -CON(R13)2-
In another embodiment, each R20 is independently -H or -(Ci-C6)alkyl.
In another embodiment, each 1120 is ¨H.
In another embodiment, each R20 is -(Ci-C6)alkyl.
In another embodiment, Ar2 is a benzothiazolyl, benzoimidazolyl, or
benzooxazolyl group; and at least one of R8 and R9 is -H.
In another embodiment, Ar2 is a benzothiazolyl, benzoimidazolyl, or
benzooxazolyl group; and at least one of R8 and R9 is not ¨H.
In another embodiment, Ar2 is a benzothiazolyl, benzoimidazolyl, or
benzooxazolyl group; and at least one of R8 and R9 is ¨halo.
In another embodiment, Ar2 is
(Ria)s
S is 1 and RI4 is -(CI-C6)alkyl, ¨halo, -C(halo)3, -0C(halo)3, -0R7, -N(R7)2, -
S02R7, or
-SO2C(halo)3.
In another embodiment, Ar2 is
vww
(R14)s 5
s is 2, and each R14 group independently is -(C1-C6)alkyl, ¨halo, -C(halo)3, -
0C(halo)3,
-0R7, -N(R7)2, -S02R7, or -S02C(hal0)3.
In another embodiment, R4 is ¨halo, n or p is 1, R7 is Q, wherein Q is
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Z3
NNW ,
wherein J is ¨0R20.
In another embodiment, R4 is ¨halo, n or p is 1, R2 is Q, wherein Q is
Z:1)71\--z3
Z2 Z3
vv.vvvws
wherein J is ¨OR70 and Z1 is -0R7.
In another embodiment, R4 is ¨halo, n or p is 1, R2 is Q, wherein Q is
Z:1),"17z3
Z2 Z3
7
wherein J is ¨0[60 and Zi is ¨CH7OR7.
In another embodiment, R4 is ¨halo, n or p is 1, R') is Q, wherein Q is
Z4
5
wherein Z4 is ¨0R20.
In another embodiment, R4 is ¨halo, n or p is 1, R7 is Q, wherein Q is
Z3
wherein J is ¨OH.
In another embodiment, R4 is ¨halo, n or p is 1, R2 is Q, wherein Q is
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Z2 Z3
wherein J is -OH and Z1 is -OH.
In another embodiment, R4 is -halo, n or p is 1, R2 is Q, wherein Q is
5
Z2 Z3
wherein J is -OH and Z1 is -CH2OH.
In another embodiment, R4 is -F, n or p is 1, R2 is Q, wherein Q is
Zix.\¨z3
Z2 Z3
vvvvvvvv.
wherein J is -OH and Z1 is -OH.
In another embodiment, R4 is -F, n or p is 1, R2 is Q, wherein Q is
Z2 Z3
wherein J is -OH and Z1 is -CH1OH.
In another embodiment, RI is -halo, R4 is -halo, n or p is 1, R1 is Q, wherein
Q is
Z3
VVVVVVV,
wherein J is -0R20.
In another embodiment, R1 is -halo, R4 is -halo, nor p is 1, R2 is Q, wherein
Q is
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Z:.1)71\¨z3
Z2 Z3
wherein J is ¨0R70 and Z1 is OR7.
In another embodiment, R1 is ¨halo, R4 is ¨halo, n or p is 1, R2 is Q, wherein
Q is
Z:õIvi\¨z3
Z2 Z3
wherein J is ¨0R20 and Z1 is ¨CH2OR7.
In another embodiment, R1 is ¨halo, R4 is ¨halo, n or p is 1, R2 is Q, wherein
Q is
,/Z4
SIVNIV NA" ,
wherein Z4 is ¨0R70.
In another embodiment, R1 is ¨Cl, R4 is ¨F, nor p is 1, R2 is Q, wherein Q is
Z3
wherein J is ¨0R20.
In another embodiment, R1 is ¨Cl, R4 is ¨F, nor p is 1, R2 is Q, wherein Q is
117 j7z3
Z2 Z3
wherein J is ¨0R70 and Zi is -0R7.
In another embodiment, R1 is ¨Cl, R4 is ¨F, nor p is 1, 1Z1 is Q, wherein Q is
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J
Zix.7-z3
Z2 Z3
vvvyww. ,
wherein J is -0R20 and Z1 is -CH2OR7.
In another embodiment, R1 is -Cl, R4 is -F, n or p is 1, R2 is Q, wherein Q is
0,/Z4
VVVVVVN.A, ,
wherein Z4 is -0R207
In another embodiment, R1 is -Cl, R4 is -F, n or p is 1, R? is Q, wherein Q is
J
Z3.,........õ, Z3
VVVY.A./NA" /
wherein J is -OH.
In another embodiment, R1 is -Cl, Rzi is -F, nor p is 1, R? is Q, wherein Q is
J
Zixj\--z3
Z2 Z3
7
wherein J is -OH and Z1 is -OH.
In another embodiment, R1 is -Cl, Rzt is -F, n or p is 1, R2 is Q, wherein Q
is
J
Zixj\¨z3
Z2 Z3
wherein J is -OH and Z1 is -CH2OH.
In another embodiment, Ari is a pyridyl group, wherein n is 1, and R2 is Q.
In another embodiment, Ari is a pyridyl group, wherein n is 1, R2 is Q, and Q
is
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z3...,õ..õõ Z3
wherein J is -OH.
In another embodiment, Ari is a pyridyl group, wherein n is 1, R2 is Q, and Q
is
Z2 Z3
wherein J is ¨0R20, and Z1 is ¨0R7.
In another embodiment, Ari is a pyridyl group, wherein n is 1, R2 is Q, and Q
is
Zyl\--z3
Z2 Z3
VVVVVVVV% 5
wherein J is ¨OH, and Z1 is ¨OH.
In another embodiment, An is a pyridyl group, wherein n is 1, R2 is Q, and Q
is
Z.õ1õ\717z 3
Z2 Z3
wherein J is ¨OR20, and Z1 is ¨CH2OR7.
In another embodiment, Ari is a pyridyl group, wherein n is 1, R,) is Q, and Q
is
Z2 Z3
vvvvvvw,
wherein J is ¨OH, and Z1 is ¨CH-,OH.
In another embodiment, An is a pyridyl group, wherein n is 1, R,.) is Q, and Q
is
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O
wherein Z4 is ¨ORM.
In another embodiment, R1 is ¨halo, R4 is ¨halo, and Ari is a pyridyl group,
wherein n is 1, R, is Q, and Q is
Z2 Z3
VVVVV1IN.AA
wherein J is ¨0R20, Z1 is ¨0R7.
In another embodiment, R1 is ¨halo, R4 is ¨halo, and An is a pyridyl group,
wherein n is 1, R, is Q, and Q is
Z:Ly.,17z3
Z2 Z3
VVVY
wherein J is ¨OH, Z1 is ¨OH.
In another embodiment, Ri is ¨halo, R4 is ¨halo, and Ari is a pyridyl group,
wherein n is 1, R2 is Q, and Q is
Zyl\--z3
Z2 Z3
wherein J is ¨0R20, Z1 is ¨CH2OR7.
In another embodiment, R1 is ¨halo, R4 is ¨halo, and Ari is a pyridyl group,
wherein n is 1, R, is Q, and Q is
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Z2 Z3
vvvvvv.
wherein J is -OH, Z1 is -CH,OH.
In another embodiment, R1 is -halo, R4 is -halo, and Ari is a pyridyl group,
5 wherein n is 1, 1Z7 is Q, and Q is
Z:_i>717z3
Z2 Z3
wherein J is -OH, Z1 is -OH, Ar2 is benzothiazolyl, wherein at least one of R8
or R9 is
10 not -H.
In another embodiment, R1 is -halo, R4 is -halo, and Ari is a pyridyl group,
wherein n is 1, R.) is Q, and Q is
Z:L>71\¨z3
Z2 Z3
vvvvv,","
wherein J is -OH, Z1 is -CH2OH, Ar2 is benzothiazolyl, wherein at least one of
R8 or R9
is not -H.
In another embodiment, R1 is -halo, R4 is -halo, and Ari is a pyridyl group,
wherein n is 1, R,) is Q, and Q is
Z2 Z3
wherein J is -OH, Z1 is -OH, Ar2 is benzooxazolyl, wherein at least one of R8
or R9 is
not -H.
In another embodiment, R1 is -halo, R4 is -halo, and An is a pyridyl group,
wherein n is 1, R2 is Q, and Q is
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Z2 Z3
wherein J is ¨OH, Z1 is ¨CH2OH, AI-) is benzooxazolyl, wherein at least one of
R8 or R9
is not ¨H.
In another embodiment, R1 is ¨halo, R4 is ¨halo, and Art is a pyridyl group,
wherein n is I, R7 is Q, and Q is
Z2 Z3
vvv,ww, 5
wherein J is ¨OH, Z1 is ¨OH, Ar2 is benzoimidazolyl, wherein at least one of
R8 or R9 is
not -H.
In another embodiment, R1 is ¨halo, R4 is ¨halo, and Art is a pyridyl group,
wherein n is 1, R7 is Q, and Q is
1.1x,17.z3
Z2 Z3
wherein J is ¨OH, Z1 is ¨CH2OH, Ar) is benzoimidazolyl, wherein at least one
of R8 or
R9 is not ¨H.
In another embodiment, R1 is ¨halo, R4 is ¨halo, and Art is a pyridyl group,
wherein n is I, R2 is Q, and Q is
Z2 Z3
wherein J is ¨OH, Z1 is ¨OH, Ar7 is phenyl, wherein s is 0 or 1.
In another embodiment, R1 is ¨halo, R4 is ¨halo, and Art is a pyridyl group,
wherein n is 1, R7 is Q, and Q is
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Z\yk_z3
Z2 Z3
wvvvvvv.
wherein J is -OH, Z1 is -CH20H, Ar2 is phenyl, wherein s is 0 or I.
In another embodiment, R1 is -halo, R4 is -halo, and Ari is a pyridyl group,
wherein n is 1, R7 is Q, and Q is
1:7,1\¨z3
Z2 Z3
wherein J is -OH, Z1 is -OH, Ar, is phenyl, wherein s is 2.
In another embodiment, R1 is -halo, R4 is -halo, and An is a pyridyl group,
wherein n is 1, R7 is Q, and Q is
Zz3
Z2 Z3
wherein J is -OH, Z1 is -CH,OH, Ar, is phenyl, wherein s is 2.
In another embodiment, the dashed line is a double bond, n or p is 1, R2 is Q,
wherein Q is
Z3
YVVVVVV,
wherein J is -0R20.
In another embodiment, the dashed line is a double bond, n or p is 1, R2 is Q,
wherein Q is
Zi))\¨z3
Z2 Z3
VVVVVVVIA
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wherein J is ¨ORD) and Z1 is OR7.
In another embodiment, the dashed line is a double bond, n or p is 1, R,) is
Q,
wherein Q is
Zix,17z3
Z2 Z3
wherein J is ¨OR70 and Z1 is ¨C1420R7.
In another embodiment, the dashed line is a double bond, n or p is 1, R2 is Q,
wherein Q is
Z4
,
wherein Z4 is ¨OR?o=
In another embodiment, the dashed line is a double bond, n or p is I, R2 is Q,
wherein Q is
Z3
vwvvvvv.
wherein J is ¨OH.
In another embodiment, the dashed line is a double bond, n or p is 1, R? is Q,
wherein Q is
Z.:).717z3
Z2 Z3
VNAARANNA
wherein J is ¨OH and Z1 is -OH.
In another embodiment, the dashed line is a double bond, n or p is 1, R,) is
Q,
wherein Q is
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Zi\v(__z3
Z2 Z3
VVNANVW.
wherein J is ¨OH and Z1 is -CfbOH.
In another embodiment, the dashed line is a double bond, R1 is ¨halo, n or p
is 1,
R2 is Q, wherein Q is
wherein J is ¨OH.
In another embodiment, the dashed line is a double bond, R1 is ¨halo, n or p
is 1,
R7 is Q, wherein Q is
Zi.xj\--z3
Z2 Z3
VVVVVW,
wherein J is ¨OH and Z1 is -OH.
In another embodiment, the dashed line is a double bond, R1 is ¨halo, n or p
is 1,
R2 is Q, wherein Q is
Zix,(¨z3
Z2 Z3
VSANNAA.M.
wherein J is ¨OH and Z1 is -CH2OH.
In another embodiment, the dashed line is a double bond, R1 is ¨halo, and Ari
is
a pyridyl group, wherein n is 1, R7 is Q, and Q is
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Z.1)7z3
Z2 Z3
wherein J is -OH, Z1 is -OH.
In another embodiment, the dashed line is a double bond, R1 is -halo, and An
is
5 a pyridyl group, wherein n is 1, 1Z2 is Q, and Q is
Z2 Z3
wherein J is -OH, Z1 is -CH2OH.
10 In
another embodiment, the dashed line is a double bond, R1 is -halo, and An is
a pyridyl group, wherein n is 1, R2 is Q, and Q is
Z:L>71\¨z3
Z2 Z3
15 wherein J is -OH, Zi is -OH Ar, is benzothiazolyl, wherein at least one
of R8 or R9 is
not a -H.
In another embodiment, the dashed line is a double bond, R1 is -halo, and An
is
a pyridyl group, wherein n is 1, R? is Q, and Q is
Z.z\¨z3
Z2 Z3
wherein J is -OH, Z1 is -CH20H, Ar-) is benzothiazolyl, wherein at least one
of R8 or R9
is not a -H.
In another embodiment, the dashed line is a double bond, R1 is -halo, and Ari
is
a pyridyl group, and Q is
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Zz3
Z2 Z3
wherein J is ¨OH, Z1 is ¨OH Ar2 is benzooxazolyl, wherein at least one of R8
or R9 is
not a ¨H.
In another embodiment, the dashed line is a double bond, R1 is ¨halo, and Ari
is
a pyridyl group, wherein n is 1, and Q is
Z2 Z3
vvwvvvv.
wherein J is ¨OH, Z1 is ¨CH,OH, Ar2 is benzooxazolyl, wherein at least one of
R8 or R9
is not a ¨H.
In another embodiment, the dashed line is a double bond, R1 is ¨halo, and An
is
a pyridyl group, wherein n is 1, R2 is Q, and Q is
Z2 Z3
wherein J is ¨OH, Z1 is ¨OH, Ar2 is benzoimidazolyl, wherein at least one of
R8 or R9 is
not a -H.
In another embodiment, the dashed line is a double bond, R1 is ¨halo, and Ari
is
a pyridyl group, wherein n is 1, R, is Q, and Q is
Z:17,k_z3
Z2 Z3
VVVVVVVNA
wherein J is ¨OH, Z1 is ¨C1-12OH, Ar2 is benzoimidazolyl, wherein at least one
of R8 or
R9 is not a ¨H.
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In another embodiment, the dashed line is a double bond, R1 is ¨halo, and An
is
a pyridyl group, wherein n is 1, R2 is Q, and Q is
Zyl\--
Z2 Z3
wherein J is ¨OH, Z1 is ¨OH Ar2 is phenyl, wherein s is 0 or 1 and R14 is -(Ci-
C6)alkyl,
¨halo, -C(halo)3, -0C(halo)3, -0R7, -N(R7)2, -SO2R7, or -S02C(halo)3, and
preferably is
¨F, -Cl, -CF3, or ¨0CF3.
In another embodiment, the dashed line is a double bond, R1 is ¨halo, and Ari
is
a pyridyl group, wherein n is 1, R2 is Q, and Q is
XJYZz3
Z2 Z3
wherein J is ¨OH, Z1 is ¨CH2OH, An) is phenyl, wherein s is 0 or 1 and R14 is
C6)alkyl, ¨halo, -C(halo)3, -0C(halo)3, -0R7, -N(R7)2, -S02R7, or -
S02C(halo)3, and
preferably is ¨F, -Cl, -CF3, or ¨0CF3..
In another embodiment, the dashed line is a double bond, R1 is ¨halo, and Ari
is
a pyridyl group, wherein n is 1, R2 is Q, and Q is
Z2 Z3
wherein J is ¨OH, Z1 is ¨OH Ar2 is phenyl, wherein s is 2, and each R14 is
independently
-(CI-C6)alkyl, ¨halo, -C(halo)3, -0C(halo)3, -0R7, -N(R7)2, -SO2R7, or -
S02C(hal0)3,
and preferably is ¨F, -Cl, -CF3, or ¨0CF3..
In another embodiment, the dashed line is a double bond, R1 is ¨halo, and Ari
is
a pyridyl group, wherein n is 1, R2 is Q, and Q is
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Zix
Z2 Z3
7
wherein J is ¨OH, Z1 is ¨CH2OH, Ar2 is phenyl, wherein s is 2, and each R14 is
independently -(Ci-C6)alkyl, ¨halo, -C(halo)3, -0C(halo)3, -0R7, -N(R7)2, -
S02R7, or
-SO2C(halo)3, and preferably is ¨F, -Cl, -CF3, or ¨0CF3..
In another embodiment Q is
wherein the compound of formula I is racemic.
In another embodiment Q is
HO,, OH
and ¨
wherein the % ee of the R enantiomer is greater than 60%.
In another embodiment Q is
OH HO,, OH
and ¨
wherein the % ee of the R enantiomer is greater than 70%.
In another embodiment Q is
HO,õOH ,OH
and ¨
wherein the % ee of the R enantiomer is greater than 80%.
In another embodiment Q is
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HO-OH Haõ OH
and 5
wherein the % ee of the R enantiomer is greater than 90%.
In another embodiment Q is
HO- HO,õ, OH
JNAJNA and .A.NYN
wherein the % ee of the R enantiomer is greater than 99%.
In another embodiment Q is
HO...õ OH HO,õ,OH
and
wherein the % ee of the S enantiomer is greater than 60%.
In another embodiment Q is
OH HO,,,.OH
and
wherein the % ee of the S enantiomer is greater than 70%.
In another embodiment Q is
OH HO,,, OH
and %IWO 5
wherein the % ee of the S enantiomer is greater than 80%.
In another embodiment Q is
OH HOE,.OH
õ., and
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wherein the % ee of the S enantiomer is greater than 90%.
In another embodiment Q is
HO.õ, OH HO,õ'OH
and ¨
5
wherein the % ee of the S enantiomer is greater than 99%.
In another embodiment, the invention encompasses compounds of formula 1.4:
Ari. .R4
R3)rn
R20
Ar2
10 (1.4)
or a pharmaceutically acceptable salt thereof, where
X is 0, S, N-CN, N-OH, or N-0R10;
W is N or C;
15 the dashed line denotes the presence or absence of a bond, and when
the dashed
line denotes the presence of a bond or W is N then R4 is absent, otherwise R4
is -H, -OH,
-0CF3, -halo, -(C1-C6)alkyl, -CH2OH, -CH2C1, -CH2Br, -CH21, -CH2F, -CH(halo)2,
-
CF3, -ORD), -SR 10, -COOH, -000R10, -C(0)R10, -C(0)H, -0C(0)R10, -0C(0)NHR to,
-
NHC(0)R13, -CON(R13)2, -S(0)2R10, or -NO2;
20 R10 is -(C1-C4)alkyl;
each R13 is independently: -H, -(Ci-C4)alkyl, -(C1-C4)alkenyl, -(CI-
C4)alkynyl, or
¨phenyl;
Ari is
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(R2)n\ _., (R2)n _ (R2)n N .,(R2)n
X N 3
1 1
RiN , R , R ....õ....,.......
i i 5 Ri
----
\ MAMMA WVVVVNA
(IRDID N (R2)P\ (R2)P
N'A N 1\1\
I
RiN , Ri/1) , R(-N 5
¨õ,¨,
,N, (R2)13, N (R2)P
N ' N '-\N
or ti
N .
R1 R1 Ri
Ar, is
\ )\---
NNN¨R20 N s N' 0
, yil (Ria)t
1
III ' II ' llik y2 R12a
R12b
R8 R9 R8 R9 R8 R9
7,
¨(R14)t I ¨(R14)t
/
Yi , Yi
1 1
Y2 ,E
Y2 Ir
\(Y3)C (Y3)C v
VVVVVVV, VVVVVVV1A VIAMANNA VVVVINAA
I , , n or
N. C
(R14)q (R14)q (R14)q (R14)S (R11)r
C is the integer 0, 1, or 2;
Yi, Y2, Y3 are independently C, N, or 0;
wherein no more than one of Y1, Y2, or Y3 can be 0, and for each Yi, Y2, and
Y3
that is N, the N is bonded to one R21 group, and for each Y1, Y2, and Y3 that
is C, the C is
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bonded to two R20 groups, provided that there are no more than a total of two
(C1-
C6)alkyl groups substituted on all of Y1, Y2, and Y3;
R12a and R12b are independently -H or -(CI-C6)alkyl;
E is =0, =S, =C(C1-05)alkyl, =C(C1-05)alkenyl, =NH(Ci-C6)alkyl, or =N-0R20;
R1 is -H, -halo, -(Ci-C4)alkyl, -NO2, -CN, -OH, -OCH3, -NH2, -C(halo)3,
-CH(halo)2, -CH2(halo), -0C(halo)3, -OCH(halo)2, or -OCH2(halo);
each R2 is independently:
(a) -halo, -OH, -0(CI-C4)alkyl, -CN, -NO2, -NH2, -(CI-Cio)alkyl, -(C2-
Cio)alkenyl, -(C2-Clo)alkynyl, -phenyl, or
(b) a group of formula Q;
wherein Q is
OZ4 07k--Z3
N.A/VVVV," VVVVVVNAA SM./V./VV.,
snru.s.Annr,
0
0 R
R20 0," R
Z3 Z3 I
Z3 , Z3 0
fvvvvwx.,
0
H,)L
N R201
0 0
HõS,
R20 N R20
Z Z3
Z2 Z3 7 Z2 Z3 or z2 Z3
15 Z1 is -H, -0R7, -SR7, -CH2-0R7, -CH2-SR7, -CH2-N(R202, or -halo;
Z2 is -H, -(C1-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, -phenyl, or -halo;
each Z3 is independently -H, -(CI-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl,
or
-phenyl;
Z4 is -H, -OH, -0R20, -(CI-C6)alkyl, or -NR20;
20 J is -0R20, -SRN, or -N(R202;
provided that at least one R2 group is a group of formula Q, and provided that
when Z1 is -0R7 or -SR7, then Z2 is not -halo;
each R3 is independently:
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(a) -H, (C1-C6)alkyl, or two R3 groups form a bicyclo group to give one
of the following structures,
Ari. -R4 Ar1.w-R4
KN)
or
N
X N X N
,R20 ,R20
Ar2 Ar2
each R7 is independently -H, -(C1-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl,
-(C3-C8)cycloalkyl, -(C5-C8)cycloalkenyl, -phenyl, -(C1-C6)haloalkyl, -(C1-
C6)hydroxyalkyl, -(C 1-C6)alkoxy(C -C6)alkyl, -(C1-C6)alkyl-N(R202, or -
CON(R20)2;
each R8 and R9 are independently -H, -(Ci-C6)alkyl, -(C2-C6)alkenyl, -(C2-
C6)alkynyl, -(C3-C8)cycloalkyl, -(C5-C8)cycloalkenyl, -phenyl, -CH2C(halo)3,-
C(halo)3,
-CH(halo)2, -CH2(halo), -0C(halo)3, -OCH(halo)2, -OCH2(halo), -0-CN, -OH, -
halo,
-N3, -NO2, -CH=NR7, -N(R7)2, -NR7OH, -0R7, -C(0)R7, -C(0)0R7, -0C(0)R7,
-0C(0)0R7, -SR7, -S(0)R7, or -S(0)2R7;
each R11 is independently -CN, -OH, -(C1-C6)alkyl, -(C2-C6)alkenyl, -halo, -
N3,
-NO2, -N(R7)2, -CH=NR7, -NR7OH, -0R7, -C(0)R7,
-C(0)0R7, -0C(0)R7, or -0C(0)0R7;
each R14 is independently -(C1-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, -
(C3-
C8)cycloalkyl, -(C5-C8)cycloalkeny1,-(C -C6)alkoxy-(C -C6)alkyl, -phenyl,
C(halo)3,
CH(halo)2, CH2(halo), -(3- to 7-membered)heterocycle, -(Ci-C6)haloalkyl, -(C2-
C6)haloalkenyl, -(C2-C6)haloalkynyl, -(C2-C6)hydroxyalkenyl, -(C2-
C6)hydroxyalkynyl,
(C1-C6)alkoxy(C2-C6)alkyl, (C1-C6)alkoxy(C2-C6)alkenyl, (C1-C6)alkoxy(C2-
C6)alkynyl,
-CN, -OH, -halo, OC(halo)3, -N3, -NO2, -CH=NR7, -N(R7)2, -NR7OH, -0R7, -SR7, -
0(CH2)b0R7, -0(CH2)bSR7, -0(CH2)bN(R7)2, -N(R7)(CF12)b0R7, -N(R7)(CH2)bSR7, -
N(R7)(CH2)bN(R7)2, -N(R7)COR7, -C(0)R7, -C(0)0R7, -0C(0)R7, -0C(0)0R7,
-S(0)R7, or -S(0)2R7, -S(0)2N(R7)2, SO2C(halo)3, -CON(R7)2, -(C1-05)alkyl-C-
NOR7, -
(CI-05)alkyl-C(0)-N(R7)2, -(C1-C6)alkyl-NHSO2N(R7)2, or -(CI-C6)alkyl-C(=NH)-
N(R7)2;
each R20 is independently -H or -(C1-C6)alkyl;
each R21 is independently -H, -(CI-C6)alkyl,
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N(C H3)2
0
o N
or s
=
each halo is independently -F, -Cl, -Br, or -I;
n is the integer 1,2, or 3;
p is the integer 1 or 2;
each b is independently the integer 1 or 2;
q is the integer 0, 1, 2, 3, or 4;
r is the integer 0, 1, 2, 3, 4, 5, or 6;
s is the integer 0, 1, 2, 3,4, or 5;
t is the integer 0, 1,2, or 3; and
m is the integer 0, 1, or 2.
In another embodiment relating to formula 1.4, E is =0, =S, =CH(CI-05)alkyl,
=CH(Ci-05)alkenyl, or =N-0R20.
In another embodiment relating to formula 1.4, E is =0, =S, or =N-0R20.
In another embodiment, the invention encompasses compounds of formula 1.3:
Ari. ,R4
(R3)m
R20
Xl\r
Ar2
(1.3)
or a pharmaceutically acceptable salt thereof, where
X is 0, S, N-CN, N-OH, or N-0R10;
W is N or C;
the dashed line denotes the presence or absence of a bond, and when the dashed
line denotes the presence of a bond or W is N then R4 is absent, otherwise R4
is -H, -OH,
-0CF3, -halo, -(Ci-C6)alkyl, -CH1OH, -CH2C1, -CH2Br, -CH2I, -CH(halo)2, -
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CF3, -0R10, -SRio, -COOH, -COORio, -C(0)Rio, -C(0)H, -0C(0)R10, -0C(0)NHR10,-
NHC(0)R13,-CON(R13)2,-S(0)2R10, or -NO2;
R10 is -(C1-C4)alkyl;
each R13 is independently: -H, -(CI-C4)alkyl, -(C1-C4)alkenyl, -(C1-
C4)alkynyl, or
5 ¨phenyl;
An is
(R2)n (R2)n (R2)n N
N
N ' /r
1
,
R11
Ri N , ' R1 ' R1
vvvur..n.rvv, VWV.AAAA V1-"JVVINV, INA.A.M.A,
( R2)P . N (R2)10. (R2)P
N\ N N\
j1
R N , R1/) ' /N ,
i R1
SNANIJNAJN VINANNA."
WV1/VV1.",
NN (R2)13\.N (R2)P\
' , \ --A N
)-(1-N2/10 , or RiINI .
Ri Ri
10 Ar2 is
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Afl
N-NN¨R20 N S
y2 R12a
V3)c R12b
R8 R9 R8 R9 R8 R9
R14)
t y
,
Y2 Y2 V
\(Y3)C E (Y3)C
VWVVVVVN VVVVVVVV, %AMMAN%
C or
(Rizi)q (Ria)ci (R14)q (R14)S (R11)r
C is the integer 0, 1, or 2;
Yi, Y2, Y3 are independently C or N;
wherein for each Y1, Y2, and Y3 that is N, the N is bonded to one R20 group,
and
for each Yi, Y2, and Y3 that is C, the C is bonded to two R20 groups, provided
that there
are no more than a total of two (C1-C6)alkyl groups substituted on all of Y1,
Y2, and Y3;
R12a and RI2b are independently ¨H or -(C1-C6)alkyl;
E is =0, =S, =C(C1-05)alkyl, =C(CI-05)alkenyl, =NH(C1-C6)alkyl, or =N-0R20;
R1 is -H, -halo, -(C1-C4)alkyl, -NO2, -CN, -OH, -OCH3, -NH2, -C(halo)3,
-CH(halo)2, -CH2(halo), -0C(halo)3, -OCH(halo)2, or -OCH2(halo);
each R2 is independently:
(a) -halo, -OH, -0(C -C4)alkyl, -CN, -NO2, -NH2, -(C1-C 0)alkyl, -(C2-
C1o)alkenyl, -(C2-C10)alkynyl, ¨phenyl, or
(b) a group of formula Q;
wherein Q is
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Zix A_ 0
Z3 Z3 C) Z4
, Z2 3, Z3
VVVVVVVVN VVVVIAAIN
0
R20 HI\R20 R
r
NH
Z3 I
---3
Z3 , Z3 0 5 Z3 5
NM-VW,
0
H,N)- R20 1
0 N 0 0
IR20 HõS,
N R20
Z3
Z2 Z3 , Z2 Z3 or z2
Z3
Z1 is -H, -0R7, -SR7, -CH2-0R7, -CH2-SR7, -CH7-N(R20)2, or -halo;
Z2 is -H, -(C1-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, -phenyl, or -halo;
each Z3 is independently -H, -(C1-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl,
or
-phenyl;
Z4 is ¨H, -OH, -0R20, -(C1-C6)alkyl, or -NR20;
J is -0R20, -SR20, or -N(R20)2;
provided that at least one R2 group is a group of formula Q, and provided that
when Z1 is ¨0R7 or ¨SR7, then Z2 is not ¨halo;
each R3 is independently:
(a) ¨H, (CI-C6)alkyl, or two R3 groups form a bicyclo group to give one
of the following structures,
Ari, R4 Ari, R4
(N) Or KN)
R20 X R20
l\r
Ar2 Ar2
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each R7 is independently -H, -(Ci-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl,
-(C3-C8)cycloalkyl, -(C5-C8)cycloalkenyl, -phenyl, -(C -C6)haloalkyl, -(C 1-
C6)hydroxyalkyl, -(C -C6)alkoxy(C -C6)alkyl, -(C1-C6)alkyl-N(R20)2, or -
CON(R20)2;
each R8 and R9 are independently -H, -(C1-C6)alkyl, -(C2-C6)alkenyl, -(C2-
C6)alkynyl, -(C3-C8)cycloalkyl, -(C5-C8)cycloalkenyl, -phenyl, -CH2C(halo)3,-
C(halo)3,
-CH(halo)2, -CH2(halo), -0C(halo)3, -OCH(halo)2, -OCH2(halo), -0-CN, -OH, -
halo,
-N3, -NO2, -CH=NR7, -N(R7)2, -NR7OH, -0R7, -C(0)R7, -C(0)0R7, -0C(0)R7,
-0C(0)0R7, -SR7, -S(0)R7, or -S(0)2R7;
each R11 is independently -CN, -OH, -(Ci-C6)alkyl, -(C2-C6)alkenyl, -halo, -
N3,
-NO2, -N(R7)2, -CH=NR7, -NR7OH, -0R7, -C(0)R7, -C(0)0R7, -0C(0)R7, or
-0C(0)0R7;
each R14 is independently -(C1-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, -
(C3-
C8)cycloalkyl, -(C5-C8)cycloalkeny1,-(CI-C6)alkoxy-(C1-C6)alkyl, -phenyl,
C(halo)3,
CH(halo)2, CH2(halo), -(3- to 7-membered)heterocycle, -(C1-C6)haloalkyl, -(C2-
C6)haloalkenyl, -(C2-C6)haloalkynyl, -(C2-C6)hydroxyalkenyl, -(C2-
C6)hydroxyalkynyl,
(CI -C6)alkoxy(C2-C6)alkyl, (CI -C6)alkoxy(C2-C6)alkenyl, (CI -C6)alkoxy(C2-
C6)alkynyl,
-CN, -OH, -halo, OC(halo)3, -N3, -NO2, -CH=NR7, -N(R7)2, -NR7OH, -0R7, -SR7, -
0(CH2)b0R7, -0(CH2)bSR7, -0(CH2)bN(R7)2, -N(R7)(CH2)b0R7, -N(R7)(CH2)bSR7, -
N(R7)(CH2)bN(R7)2, -N(R7)COR7, -C(0)R7, -C(0)0R7, -0C(0)R7, -0C(0)0R7,
-S(0)R7, or -S(0)2R7, -S(0)2N(R7)2, SO2C(halo)3, -CON(R7)2, -(C1-05)alkyl-C-
NOR7, -
(C1-05)alkyl-C(0)-N(R7)2, -(C1-C6)alkyl-NNSO2N(R7)2, or -(C1-C6)alkyl-C(=NH)-
N(R7)2;
each R20 is independently -H or -(C1-C6)alkyl;
each halo is independently -F, -Cl, -Br, or -1;
n is the integer 1,2, or 3;
p is the integer 1 or 2;
each b is independently the integer 1 or 2;
q is the integer 0, 1, 2, 3, or 4;
r is the integer 0, 1, 2, 3,4, 5, or 6;
s is the integer 0, 1, 2, 3, 4, or 5;
t is the integer 0, 1, 2, or 3; and
in is the integer 0, 1, or 2.
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In another embodiment relating to formula 1.3, E is =0, =S, =CH(C1-05)alkyl,
=CH(CI-05)alkenyl, or =N-0R20.
In another embodiment relating to formula 1.3, E is =0, =S, or =N-0R20.
In another embodiment, the invention encompasses compounds of formula 1.2:
AriõR4
T(R3)m
R20
Ar2
(I.2)
or a pharmaceutically acceptable salt thereof, where
Xis 0, S, N-CN, N-OH, or N-0R10;
W is N or C;
the dashed line denotes the presence or absence of a bond, and when the dashed
line denotes the presence of a bond or W is N then R4 is absent, otherwise R4
is -H, -OH,
-0CF3, -halo, -(C1-C6)alkyl, -CH2OH, -CF2C1, -CH2Br, -CH21, -CH2F, -CH(halo)2,
-
CF3, -COOH, -
000R10, -C(0)R10, -C(0)H, -0C(0)R10, -0C(0)NHR10,-
NHC(0)R13,-CON(R13)2,-S(0)2R10, or -NO2;
R10 is -(C1-C4)alkyl;
each R13 is independently: -H, -(C1-C4)alkyl, -(C1-C4)alkenyl, -(C1-
C4)alkynyl, or
¨phenyl;
Ari is
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(R2)n (R2)n _ (R2)n .N (R2)n
r\ 11\1 N '
N, , R1 .,j ,I ,
R1 R1 R1
----,
(R2)P =N (R2)P,\-- (R2)P
N =\- N N'\
I
, Ri/lj
Ri R1
N
,N (R2)1D (R2)13
, or N
Ri R1 R1 ;
Ar2 is
WV, WV,
)7
7;
NN¨R20 N 7 s NXID
(R14 )t
I
1111 ' 111 ' 11, y2 R12a
\(y3)c R12b
R8 R9 R8 R9 R8 R9
7; \
I .----(R14)t
/
Yr
E , Yi
I I
Y2 Y2 V
\(Y3)c (Y3)c
VVVV,/,/, VVVVVVV, WWWV, WVVVVV, WWWW,
N /--
I ' I , I , I or
(p.0
(R14)q (Ria)ci \'µ14)ci (Ria)s (Rii)r
5 =
c is the integer 0, I, or 2;
Yi, Y2, Y3 are independently C or N;
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wherein for each Y1, Y2, and Y3that is N, the N is bonded to one R20 group,
and
for each Yi, Y2, and Y3 that is C, the C is bonded to two R20 groups, provided
that there
are no more than a total of two (CI-C6)alkyl groups substituted on all of Yi,
Y2, and Y3;
RI2a and R12b are independently -H or -(C1-C6)alkyl;
E is =0, =S, =C(CI-05)alkyl, =C(C1-05)alkenyl, =NH(C1-C6)alkyl, or =N-0R20;
R1 is -H, -halo, -(C1-C4)alkyl, -NO2, -CN, -OH, -OCH3, -NH2, -C(halo)3,
-CH(halo)2, -CH2(halo), -0C(halo)3, -OCH(halo)2, or -OCH2(halo);
each R2 is independently:
(a) -halo, -OH, -0(CI-C4)alkyl, -CN, -NO2, -NH2, -(C1-C 0)alkyl, -(C2-
C 0)alkenyl, -(C2-C o)alkynyl, -phenyl, or
(b) a group of formula Q;
wherein Q is
Z3 Zy Z3 () Z4 07\-Z3
vv-vvvvvvk vvvvLnn.n"
0 R
R20 R
Z3 Z3
, I
3,1NH
Z3 Z3 0 Z
0
II
H,
0 0
N R20 IR20 N R20
Z3 Z3 Zi Z3
Z2 Z3 , Z2 Z3 or Z2
Z3
Zi is -H, -0R7, -SR7, -CH2-SR7, -CH2-N(R202, or -halo;
Z2 is -H, -(C1-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, -phenyl, or -halo;
each Z3 is independently -H, -(C1-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl,
or
-phenyl;
Z4 is -H, -OH, -0R20, -(CI-C6)alkyl, or -NR20;
J is -0R20, -SR20, or -N(R202;
provided that at least one R2 group is a group of formula Q, and provided that
when Z1 is -0R7 or -SR7, then Z2 is not -halo;
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each R3 is independently:
(a) -H, (C1-C6)alkyl, or two R3 groups form a bicyclo group to give one
of the following structures,
Ari. -R4 Ari,w-R4
(N)
or
N
X N X N
,R2o ,R20
Ar2 Ar2
each R7 is independently -H, -(C1-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl,
-(C3-C8)cycloalkyl, -(C5-C8)cycloalkenyl, -phenyl, -(CI-C6)haloalkyl, -(C1-
C6)hydroxyalkyl, -(ci-C6)alkoxy(C1-C6)alkyl, -(C i-C6)alkyl-N(R2o)2, or -
CON(R20)2;
each R8 and R9 are independently -H, -(CI-C6)alkyl, -(C2-C6)alkenyl, -(C2-
C6)alkynyl, -(C3-C8)cycloalkyl, -(C5-C8)cycloalkenyl, -phenyl, -CH2C(halo)3,-
C(halo)3,
-CH(halo)2, -CH2(halo), -0C(halo)3, -OCH(halo)2, -OCH2(halo), -0-CN, -OH, -
halo,
-N3, -NO2, -CH=NR7, -N(R7)2, -NR7OH, -0R7, -C(0)R7, -C(0)0R7, -0C(0)R7,
-0C(0)0R7, -SR-y, -S(0)R7, or -S(0)2R7;
each R11 is independently -CN, -OH, -(C1-C6)alkyl, -(C2-C6)alkenyl, -halo, -
N3,
-NO2, -N(R7)2, -CH=NR7, -NR7OH, -0R7, -C(0)R7,
-C(0)0R7, -0C(0)R7, or -0C(0)0R7;
each R14 is independently -(CI-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, -
(C3-
C8)cycloalkyl, -(C5-C8)cycloalkeny1,-(C -C6)alkoxy-(CI-C6)alkyl, -phenyl,
C(halo)3,
CH(halo)2, CH2(halo), -(3- to 7-membered)heterocycle, -(C1-C6)haloalkyl, -(C2-
C6)haloalkenyl, -(C2-C6)haloalkynyl, -(C2-C6)hydroxyalkenyl, -(C2-
C6)hydroxyalkynyl,
(C1-C6)alkoxy(C2-C6)alkyl, (CI-C6)alkoxy(C2-C6)alkenyl, (CI-C6)alkoxy(C2-
C6)alkynyl,
-CN, -OH, -halo, OC(halo)3, -N3, -NO2, -CH=NR7, -N(R7)2, -NR7OH, -0R7, -SR7, -
0(CH2)b0R7, -0(CH2)bSR7, -0(CH2)bN(R7)2, -N(R7)(CH2)b0R7, -N(R7)(CH2)bSR7, -
N(R7)(CH2)bN(R7)2, -N(R7)COR7, -C(0)R7, -C(0)0R7, -0C(0)R7, -0C(0)0R7,
-S(0)R7, or -S(0)2R7, -S(0)2N(R7)2, SO2C(halo)3, -CON(R7)2, -(C1-05)alkyl-C-
NOR7, -
(C1-05)alkyl-C(0)-N(R7)2, -(C1-C6)alkyl-NHSO2N(R7)2, or -(C1-C6)alkyl-C(=NH)-
N(R7)2;
each R20 is independently -H or -(C1-C6)alkyl;
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each halo is independently -F, -Cl, -Br, or -I;
n is the integer 1, 2, or 3;
p is the integer 1 or 2;
each b is independently the integer 1 or 2;
q is the integer 0, 1, 2, 3, or 4;
r is the integer 0, 1, 2, 3, 4, 5, or 6;
s is the integer 0, 1, 2, 3, 4, or 5;
t is the integer 0, 1, 2, or 3; and
m is the integer 0, 1, or 2.
In another embodiment relating to formula 1.2, E is =0, =S, =CH(CI-05)alkyl,
=CH(CI-05)alkenyl, or =N-0R20.
In another embodiment relating to formula 1.2, E is =0, =S, or =N-0R20.
In another embodiment, the invention encompasses compounds of formula 1.1:
Ari.w,R4
.(R3)rn
,R2
X = N 0
Ar2
(I.1)
or a pharmaceutically acceptable salt thereof, where
X is 0, S, N-CN, N-OH, or N-0R10;
W is N or C;
the dashed line denotes the presence or absence of a bond, and when the dashed
line denotes the presence of a bond or W is N then R4 is absent, otherwise R4
is -H, -OH,
-0CF3, -halo, -(C1-C6)alkyl, -CH2OH, -CH2C1, -CH2Br, -CH2I, -CH2F, -CH(halo)2,
-
CF3, -0R10, -SRI , -COOH, -COORio, -C(0)R10, -C(0)H, -0C(0)R10, -0C(0)NFIR10, -
NHC(0)R13, -CON(R13)2, -S(0)2R10, or -NO2;
R10 is -(C1-C4)alkyl;
each R13 is independently: -H, -(C1-C4)alkyl, -(C1-C4)alkenyl, -(Ci-
C4)alkynyl, or
-phenyl;
Ari is
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(R2)fl
Th (R2)p (R2 )p .N (R2)
I II ii
N , RiN , RiN
or RiN ;
Ri
WA/WM \AINAAMAA WAA.A/NAJN
WAA.A/V1A
Ar2 is
NN¨R20 N-\s N \r-)
¨ I .--(R14)t
ilk
1
Y2, R
Ri2a
(y3)C 12b
R8 R9 R8 R9 R8 R9
\
I (Ria)t I (Ria)t
Y1 ' Y1
i i
Y2 Y2 W
\(Y3)C E (Y3)c v
1/1/1./W \ AAA 1.M.AAAMIN 1. AMINAMA 1/1.AAAAMA VW/WM
N
N , I , I j or
....\--- . \..,
(R14)q (Ria)q N (Ria)ci (R14)s (Ri Or
C is the integer 0, 1, or 2;
Y1, Y2, Y3 are independently C or N;
wherein for each Yi, Y2, and Y3 that is N, the N is bonded to one R20 group,
and
for each Yi, Y2, and Y3 that is C, the C is bonded to two R20 groups, provided
that there
are no more than a total of two (C1-C6)alkyl groups substituted on all of Y1,
Y2, and Y3;
RI2a and R12b are independently ¨H or -(C1-C6)alkyl;
E is =0, ----S, --C(C1-05)alkyl, =C(CI-05)alkenyl, =NH(C1-C6)alkyl, or =N-
0R20;
R1 is -H, -halo, -(C1-C4)alkyl, -NO2, -CN, -OH, -OCH3, -NH2, -C(halo)3,
-CH(halo)2, -CH2(halo), -0C(halo)3, -OCH(halo)2, or -OCH2(halo);
each R2 is independently:
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(a) -halo, -OH, -0(CI-C4)alkyl, -CN, -NO2, -NH2, -(CI-C i0)alkyl, -(C2-
C10)alkenyl, -(C2-C 10)alkynyl, -phenyl, or
(b) a group of formula Q;
wherein Q is
5
Z1-Z3 () Z4 OZ3
0
0 R
20 HN.R20 O4R2O
Z3 Z>-.NH
3 I
Z3 , Z3 0 , Z3
0
H,
C) N 0 0
N R20 IR20 HõS,
N R20
Z3
Z2 Z3 , Z2 Z3 , z2
Z3
Z1 is -H, -0R7, -SR7, -CH2-0R7, -CH2-SR7, -CH2-N(R20)2, or -halo;
Z2 is -H, -(C1-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, -phenyl, or -halo;
10 each Z3 is independently -H, -(C1-C6)alkyl, -(C2-C6)alkenyl, -(C2-
C6)alkynyl, or
-phenyl;
Z4 is -H, -OH, -0R20, -(CI-C6)alkyl, or -NR20;
J is -0R20, -SR20, or -N(R202;
provided that at least one R2 group is a group of formula Q, and provided that
15 when Z1 is -0R7 or -SR7, Z2 in not -halo;
each R3 is independently:
(a) -H, (C1-C6)alkyl, or two R3 groups may form bicyclo group, which
gives the following structures,
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Ar1.w-R4 Ari. -R4
(N) or
-R20 R20
X N X N
Ar2 Ar2
each R7 is independently -H, -(CI-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl,
-(C3-C8)cycloalkyl, -(C5-C8)cycloalkenyl, -phenyl, -(C1-C6)haloalkyl, -(Ci-
C6)hydroxyalkyl, -(c1-C6)alkoxy(Ci-C6)alkyl, -(C1-C6)alkyl-N(R20)2, or -
CON(R20)2;
each R8 and R9 are independently -H, -(C1-C6)alkyl, -(C2-C6)alkenyl, -(C2-
C6)alkynyl, -(C3-C8)cycloalkyl, -(C5-C8)cycloalkenyl, -phenyl, -CH2C(halo)3,-
C(halo)3,
-CH(halo)2, -CH2(halo), -0C(halo)3, -OCH(halo)2, -OCH2(halo), -0-CN, -OH, -
halo,
-N3, -NO2, -CH=NR7, -N(R7)2, -NR7OH, -0R7, -C(0)R7, -C(0)0R7, -0C(0)R7,
-0C(0)0R7, -SR7, -S(0)R7, or -S(0)2R7;
each Rii is independently -CN, -OH, -(CI-C6)alkyl, -(C2-C6)alkenyl, -halo, -
N3,
-NO2, -N(R7)2, -CH=NR7, -NR7OH, -0R7, -C(0)R7, -C(0)0R7, -0C(0)R7, or
-0C(0)0R7;
each R14 is independently -(C1-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, -
(C3-
C8)cycloalkyl, -(C5-C8)cycloalkeny1,-(CI-C6)alkoxy-(CI-C6)alkyl, -phenyl,
C(halo)3,
CH(halo)2, CH2(halo), -(3- to 7-membered)heterocycle, -(C1-C6)haloalkyl, -(C2-
C6)haloalkenyl, -(C2-C6)haloalkynyl, -(C2-C6)hydroxyalkenyl, -(C2-
C6)hydroxyalkynyl,
-(C1-C6)alkoxy(C2-C6)alkyl, -(C -C6)alkoxy(C2-C6)alkenyl, -(CI -C6)alkoxy(C2-
C6)alkynyl, -CN, -OH, -halo, OC(halo)3, -N3, -NO2, -CH=NR7, -N(R7)2, -NR7OH, -
0R7,
-SR7, -0(CH2)b0R7, -0(CH2)bSR7, -0(CH2)bN(R7)2, -N(R7)(CH2)b0R7, -
N(R7)(CH2)bSR7, -N(R7)(CH2)bN(R7)25-N(R7)COR7, -C(0)R7, -C(0)0R7, -0C(0)R7,
-0C(0)0R7, -S(0)R7, or -S(0)2R7, -S(0)2N(R7)2, SO2C(halo)3, -CON(R7)2, -(Ci-
C5)alkyl-C=NOR7, -(C1-05)alkyl-C(0)-N(R7)2, -(C1-C6)alkyl-NHSO2N(R7)2, or -(C1-
C6)alkyl-C(=NH)-N(R7)2;
each R20 is independently -H or -(C1-C6)alkyl;
each halo is independently -F, -Cl, -Br, or -I;
n is the integer 1, 2, or 3;
p is the integer 1 or 2;
each b is independently the integer 1 or 2;
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q is the integer 0, 1, 2, 3, or 4;
r is the integer 0, 1, 2, 3, 4, 5, or 6;
s is the integer 0, 1, 2, 3, 4, or 5;
t is the integer 0, 1,2, or 3; and
m is the integer 0, 1, or 2.
In another embodiment relating to formula 1.1, E is =0, =S, =CH(C1-05)alkyl,
=CH(C1-05)alkenyl, or =N-0R20.
In another embodiment relating to formula 1.1, E is =0, =S, or =N-0R20.
In other embodiments, the compound of formula I is
HO OH
HO H0444....)
flCI
CI
)
ONH N
ONH (:)NH
1001 1401
OCF3 CF3
Q5 S5 R6
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N
NH2
CN
Th 1 1
N
CI,N N
CI CI
N
oNH oNH ONH
1.1 0 lei
CF3 CF3 or , OC F3 .
,
S6 U6
T6
Other compounds of interest include
1 CI
CI N ,N N
F F N
O NH oNH oNH oNH
0 * 1.1 *
F CI
CF3 OC F3 CF3 CF3
213 214 208 215
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FN N N N
CI CI
/2(
HNO ONH NHNH
NH
SF
1401 14111
CF3 CF3 0 ¨S __ 0 OCF3 , and CF3
'
212 209 211 207
CF3
210
Aqueous solubility of compounds is often a desirable feature. For example,
aqueous solubility of a compound permits that compound to be more easily
formulated
into a variety of dosage forms that may be administered to an animal. When a
compound is not fully soluble in the blood, it may precipitate in the blood,
and the
animal's exposure to the drug will accordingly not correspond to the
administered dose.
Aqueous solubility increases the likelihood that a compound will not
precipitate in an
animal's blood, and increases the ability to predict exposure at the target
sight of the
compound.
Compounds of formula I are highly soluble in aqueous solution. For example, at
either pH 6.8 or pH 1.2, compound 200 isinsoluble in aqueous solution, i.e.,
has an
aqueous solubility <0.1 IAM. In contrast, the aqueous solubility at pH 6.8, in
M, of
compounds of formula I F2, E6, F6, and G2 is 3.0, 9.0, 9.2, and 38.2,
respectively. The
aqueous solubility at pH 1.2, in 1AM, of compounds of formula I F2, E6, F6 and
G2 is
1.0, 27.2, >50 and >50, respectively. Additionally, the aqueous solubility at
either pH
6.8 or pH 1.2 of each of compounds of formula I G6, 116, J2, and Z1 is >50
p.M. The
following compounds are aqueous insoluble at pH 6.8: 203, 207, 200, and 208.
The
following compounds have very low aqueous solubility at pH 6.8: 209, 210, 211,
212,
213, 214, and 215 have aqueous solubility, in p.M, of 1.0, 0.4, 0.4, 1.9, 0.8,
1.8, and 0.6,
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respectively. The aqueous solubility, in 04, at pH 1.2 of compounds 209, 210,
211,
212, 213, 214 and 215 is 9.3, 2.0, 1.3, 10.3, 39.6, >50 and 9.6, respectively.
In contrast,
the aqueous solubility at pH 6.8, in 04, of compounds of formula I Ni, Fl, Cl,
Y3, and
U3 is 28.0, 22.6, 15.7, 17.4, and 26.4, respectively.At pH 1.2, compounds of
formula I
5 Ni, F1, Cl, Y3 and U3 all have an aqueous solubility of >50 p.M. The
aqueous
solubility, at either pH 6.8 or pH 1.2, is >50 .M for each of the following
compounds of
formula I: H1, N6, Z1, Si, E2, and Ul.
5.2 COMPOUNDS OF FORMULA II
Preferred compounds of formula I are compounds of formula II:
R4
-7( R3),
R
X 1\ 20r
Ar2
(II)
or a pharmaceutically acceptable derivative thereof, where the dashed line, W,
X, Ari,
Ar2, R35 R45 R20, and m are as defined above for compounds of formula I,
wherein Q is
zi
Zi Z3
Z1 is -OH, -SH, -N(R20)2, -CH2-0H, -CH2-SH, or -CF2-N(R20)2;
Z2 is ¨H, -CH3, or -CH2-0R7;
each Z3 is independently ¨H or ¨CH3; and
J is -OH, -SH, or -N(R20)2.
In addition to being highly soluble in aqueous solution, compounds of formula
II
are preferred because side effects are less severe (e.g., attenuation or
removal of central
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nervous system side effects) in animals administered a compound of formula II.
For
example, muscle relaxation is attenuated or absent in animals administered a
compound
of formula II. Sedation is attenuated or absent in animals administered a
compound of
formula II. Ataxia is attenuated or absent in animals administered a compound
of
formula II. Flat body posture is attenuated or absent in animals administered
a
compound of formula II. Tremor is attenuated or absent in animals administered
a
compound of formula II. When a compound induces less severe side effects, the
therapeutic index, which is the difference between an effective dose and a
dose that
causes adverse effects, is increased. Therapeutic index is a measure of the
safety of a
compound when administered to an animal. The greater the therapeutic index,
the safer
the compound.
Compounds of formula II also have excellent pharmacokinetic properties.
Specifically, the plasma level of a compound of formula II in an animal is
dose
proportionate. Therefore, the amount of compound in the plasma of an animal
can be
more readily controlled according to the dose of the compound administered to
the
animal. Moreover, for a given dose administered, the animal plasma
concentration is
greater and is achieved more rapidly for a compound of formula II. For
example;
compound 200 achieves its maximum plasma concentration 3.1 h after
administration.
In contrast, compound of formula II Z1 achieves its maximum plasma
concentration 2.5
h after administration and that maximum plasma concentration is 2.5 times
greater than
the maximum for compound 200. Additionally, compound of formula II R6 achieves
its
maximum plasma concentration 1.85 h after administration and that maximum
plasma
concentration is 5.3 times greater than the maximum for compound 200. For each
of
compounds of formula II Z1 and R6, the plasma concentration up to 24 h is
consistently
greater for each when compared with compound 200.
Compound R6 has the following structure:
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OH
ONH
CF,
Compounds of formula II are also preferred because they have a high
therapeutic
index. Therapeutic index is the difference between the amount of a compound
that is
effective for treating a Condition and the amount of that same compound that
induces
adverse effects.
Other embodiments of formula II are presented below.
In one embodiment, a compound of formula II is a pharmaceutically acceptable
derivative of a compound of formula II.
In another embodiment, a compound of formula II is a compound of formula II
whererein the derivative is a pharmaceutically acceptable salt.
In another embodiment, a compound of formula II is a pharmaceutically
acceptable salt of a compound of formula II.
In another embodiment, Ari is a pyridyl group.
In another embodiment, Ari is a pyrimidinyl group.
In another embodiment, Ari is a pyrazinyl group.
In another embodiment, Ari is pyridazinyl group.
In another embodiment, W is C.
In another embodiment, W is N.
In another embodiment, X is 0.
In another embodiment, X is S.
In another embodiment, X is N-CN.
In another embodiment, X is N-OH.
In another embodiment, X is N-ORio.
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In another embodiment, Ar2 is a benzoimidazolyl group.
In another embodiment, Ar2 is a benzothiazolyl group.
In another embodiment, An2 is a benzooxazolyl group.
In another embodiment, Ar2 is
YVVVVVVY,
(Ria)ci.
In another embodiment, Ar2 is
VNAMJNAJNA
(Ria)q.
In another embodiment, Ar2 is
vvw
(R14)s .
In another embodiment, Ar2 is
(R14 )q
In another embodiment, Ar2 is
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(Rii)r
In another embodiment, n or p is 1.
In another embodiment, n or p is 2.
In another embodiment, n is 3.
In another embodiment, m is 2.
In another embodiment, two R3 groups together form a (C2-C6)bridge, which is
unsubstituted or substituted with 1, 2 or 3 independently selected R8 groups,
and which
bridge optionally contains -HC=CH- within the (C2-C6)bridge.
In another embodiment, two R3 groups together form a (C2-C6)bridge, which is
unsubstituted or substituted with an R8 group, and which bridge optionally
contains
-HC=CH- within the (C2-C6)bridge.
In another embodiment, two R3 groups together form a (C7-C3)bridge, which is
unsubstituted or substituted with an R8 group, and which bridge optionally
contains
-HC=CH- within the (C2-C3)bridge.
In another embodiment, two R3 groups together form a (C2-C3)bridge, which is
unsubstituted and which bridge optionally contains -HC=CH- within the (C2-
C3)bridge.
In another embodiment, two R3 groups together form a (C2)bridge, a -HC=CH-
bridge, or a (C3)bridge each of which is unsubstituted.
In another embodiment, two R3 groups together form a (C2-C6)bridge, which is
unsubstituted or substituted with 1, 2 or 3 independently selected R8 groups,
which
bridge optionally contains -HC=CH- within the (C2-C6)bridge, and which bridge
joins
positions 2 and 6 of the piperidine, 1,2,3,6-tetrahydropyridine or piperazine
ring.
In another embodiment, two R3 groups together form a (C2-C6)bridge, which is
unsubstituted or substituted with an R8 group, which bridge optionally
contains
-HC=CH- within the (C2-C6)bridge, and which bridge joins positions 2 and 6 of
the
piperidine, I ,2,3,6-tetrahydropyridine or piperazine ring.
In another embodiment, two R3 groups together form a (C2-C3)bridge, which is
unsubstituted or substituted with an R8 group, which bridge optionally
contains
-HC=CH- within the (C2-C3)bridge, and which bridge joins positions 2 and 6 of
the
piperidine, 1 ,2,3,6-tetrahydropyridine or piperazine ring.
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In another embodiment, two R3 groups together form a (C2-C3)bridge, which is
unsubstituted, which bridge optionally contains -HC=CH- within the (C2-
C3)bridge, and
which bridge joins positions 2 and 6 of the piperidine, 1,2,3,6-
tetrahydropyridine or
piperazine ring.
5 In
another embodiment, two R3 groups together form a (C2)bridge, a -HC=CH-
bridge, or a (C3)bridge each of which is unsubstituted, and which bridge joins
positions
2 and 6 of the piperidine, 1,2,3,6-tetrahydropyridine or piperazine ring.
In another embodiment, two R3 groups together form a -CH2-N(Ra)-CH2- bridge
(B1), a
Rb Rb
C-0 0= S=0
¨ CH2 -N-CH2- bridge (B2), or a ¨cH2¨N¨CH2¨ bridge (B3);
wherein Ra is selected from -H, -(CI-C6)alkyl, -(C3-C8)cycloalkyl, -CH2-C(0)-
Re, -(CH2)-C(0)-OR,, -(CH2)-C(0)-N(Rc)2, -(CH2)2-0-Re, -(CH2)2-S(0)2-N(Rc)2,
or
-(CH2)2-N(R)S(0)2-R;
Rh is selected from:
(a) -H, -(Ci-C6)alkyl, -(C3-C8)cycloalkyl, -(3- to 7-
membered)heterocycle, -N(Re)2, -N(Re)-(C3-C8)cycloalkyl, or -N(Re)-(3- to 7-
membered)heterocycle; or
(b) ¨phenyl, -(5- or 6-membered)heteroaryl, -N(R)-phenyl, or
to 10-membered)heteroaryl, each of which is unsubstituted or substituted with
1, 2 or 3
independently selected R7 groups; and
each Re is independently selected from -H or -(C1-C4)alkyl;
In another embodiment, the B1, B2, or B3 bridge joins positions 2 and 6 of the
piperidine, 1,2,3,6-tetrahydropyridine or piperazine ring.
In another embodiment, two R3 groups form a bicyclo group to give one of the
following structures,
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Ari. .R4 Ari. , R4
or (¨N)
R R
i\ 20 r )d20.1\r
Ar2 Ar2
In another embodiment, in is 1.
In another embodiment, m is 0.
In another embodiment, s or q is 0.
In another embodiment, s or q is I.
In another embodiment, s or q is 2.
In another embodiment, R1 is -H.
In another embodiment, R1 is -halo.
In another embodiment, R1 is -Cl.
In another embodiment, R1 is -F.
In another embodiment, R1 is -CH3.
In another embodiment, RI is -NO2.
In another embodiment, R1 is -CN.
In another embodiment, R1 is -OH.
In another embodiment, R1 is -OCH3.
In another embodiment, R1 is -NH".
In another embodiment, R1 is -C(halo)3.
In another embodiment, R1 is CF3.
In another embodiment, R1 is -CH(halo)2.
In another embodiment, R1 is -CH,(halo).
In another embodiment, Ari is a pyridyl group and n is 1.
In another embodiment, Ari is a pyrazinyl group and p is 1.
In another embodiment, Ari is a pyrimidinyl group and p is 1.
In another embodiment, An is a pyridazinyl group and p is 1.
In another embodiment, Q is
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OH OH OH OH OH
HO,õ.) HO HO>)
vvvõ.. ' MANN/NA
OH OH OH OH
F)) HOõ,
or OH
In another embodiment, J is ¨0R20.
In another embodiment, J is ¨OH.
In another embodiment, Z1 is ¨0R7.
In another embodiment, Z1 is ¨OH.
In another embodiment, Zi is ¨ CH7-0R7.
In another embodiment, Z1 is ¨CH7OH.
In another embodiment, Z7 is -CH2-0R7.
In another embodiment, Z7 is -CH7OH.
In another embodiment, Z7 is ¨H or -CH3.
In another embodiment, Z7 is ¨H.
In another embodiment, Z2 is ¨CH3.
In another embodiment, Z3 is ¨H.
In another embodiment, Z3 is ¨CH3.
In another embodiment, m is 1 and R3 is -(Ci-C6)alkyl.
In another embodiment, m is 1 and R3 is -CH3.
In another embodiment, R4 is -OH.
In another embodiment, R4 is -0CF3
In another embodiment, R4 is -halo.
In another embodiment, R4 is -F.
In another embodiment, R4 is -Cl.
In another embodiment, R4 is -(C1-C6)alkyl.
In another embodiment, R4 is -CH3.
In another embodiment, R4 is -CH7OH.
In another embodiment, R4 is -CH7C1.
In another embodiment, R4 is -CH713r.
In another embodiment, R4 is -CH21.
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In another embodiment, R4 is -CH2F.
In another embodiment, R4 is -CH(halo)2.
In another embodiment, R4 is -CF3.
In another embodiment, R4 is -NO2.
In another embodiment, R4 is -0R10.
In another embodiment, R4 is -SRIO.
In another embodiment, R4 is -C(0)R10.
In another embodiment, R4 is -COOH.
In another embodiment, R4 is -C(0)H.
In another embodiment, R4 is -COORio.
In another embodiment, R4 is -0C(0)R10.
In another embodiment, R4 is -S02R10.
In another embodiment, R4 is -0C(0)NFIRI0.
In another embodiment, R4 is -NHC(0)R13.
In another embodiment, R4 is -CON(R13)2.
In another embodiment, each R20 is independently -H or -(Ci-C6)alkyl.
In another embodiment, each R20 is independently ¨H or -(C3-C8)cycloalkyl.
In another embodiment, each R/0 is independently -(Ci-C6)alkyl or -(C3-
C8)cycloalkyl.
In another embodiment, each R20 is ¨H.
In another embodiment, each Rm is -(C1-C6)alkyl.
In another embodiment, each R20 is -(C3-C8)cycloalkyl.
In another embodiment, Ar, is a benzothiazolyl, benzoimidazolyl, or
benzooxazolyl group; and at least one of R8 and R9 is -H.
In another embodiment, Ar2 is a benzothiazolyl, benzoimidazolyl, or
benzooxazolyl group; and at least one of Rg and R9 is not ¨H.
In another embodiment, Ar, is a benzothiazolyl, benzoimidazolyl, or
benzooxazolyl group; and at least one of R8 and R9 is ¨halo.
In another embodiment, Arl is
(R14)s ,
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s is 1 and R14 is -(C1-C6)alkyl, ¨halo, -C(halo)3, -0C(halo)3, -0R7, -N(R7)2, -
S02R7, or
-S02C(halo)3.
In another embodiment, Ar2 is
VVVVVVVVN
(R14)S
s is 2, and each R14 group independently is -(CI-C6)alkyl, ¨halo, -C(halo)3, -
0C(halo)3,
-0R7, -N(R7)2, -S02R7, or -S02C(hal0)3.
In another embodiment, J is ¨OH, and Zi is ¨OH.
In another embodiment, J is ¨OH and Z1 is ¨CH2OH.
In another embodiment, J is ¨OH, Z1 is ¨OH, Z2 is ¨H, and Z3 is ¨H.
In another embodiment, J is ¨OH, Zi is ¨CH2OH, Z2 is ¨H, and Z3 is ¨H.
In another embodiment, Rit is ¨halo, J is ¨OH, Z1 is ¨OH, Z7 is ¨H, and Z3 is
¨H.
In another embodiment, R4 is ¨halo, J is ¨OH, Z1 is ¨CH2OH, Z2 is ¨H, and Z3
is
¨H.
In another embodiment, R4 is ¨F, J is ¨OH, Z1 is ¨OH, Z2 is ¨H, and Z3 is ¨H.
In another embodiment, R4 is ¨F, J is ¨OH, Z1 is ¨CH2OH, Z2 is ¨H, and Z3 is
-H.
In another embodiment, RI is ¨halo, R4 is ¨halo, J is ¨OH, Z1 is ¨OH, Z2 is
¨H,
and Z3 is ¨H.
In another embodiment, R1 is ¨halo, R4 is ¨halo, J is ¨OH, Zi is ¨CH2OH, Z2 is
-H, and Z3 is ¨H.
In another embodiment, R1 is ¨Cl, R4 is ¨F, J is ¨OH, Z1 is ¨OH, Z7 is ¨H, and
Z3 is ¨H.
In another embodiment, R1 is ¨Cl, R4 is ¨F, J is ¨OH, Z1 is ¨CH2OH, Z2 is ¨H,
and Z3 is ¨H.
In another embodiment Ari is
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In another embodiment, R1 is ¨halo, R4 is ¨halo, Ari is
Ri
5
J is ¨OH, Z1 is ¨OH, Z2 is ¨H, and Z3 is ¨H.
In another embodiment, R1 is ¨halo, R4 is ¨halo, Ari is
R1
1 0
J is ¨OH, Z1 is ¨CH2OH, Z2 is ¨H, and Z3 is ¨H.
In another embodiment, R1 is ¨halo, R4 is ¨halo, Ari is
R1
J is ¨OH, Zi is ¨OH, Z, is ¨H, Z3 is ¨H, Ar2 is benzooxazolyl, wherein at
least one of R8
or R9 IS not ¨H.
In another embodiment, R1 is ¨halo, R4 is ¨halo, An is
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J is ¨OH, Z1 is ¨CH2OH, Z2 is ¨H, Z3 is ¨H, Ar2 is benzooxazolyl, wherein at
least one
of R8 or R9 is not ¨H.
In another embodiment, R1 is ¨halo, R4 is ¨halo, Ari is
Ri
J is ¨OH, Z1 is ¨OH, Z2 is ¨H, Z3 is ¨H, Ar2 is benzothiazolyl, wherein at
least one of R8
or R9 iS not ¨H.
In another embodiment, R1 is ¨halo, R4 is ¨halo, An is
Ri
J is ¨OH, Z1 is ¨CH2OH, Z2 is ¨H, Z3 is ¨H, Ar2 is benzothiazolyl, wherein at
least one
of R8 or R9 is not ¨H.
In another embodiment, R1 is ¨halo, R4 is ¨halo, An is
Ri
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J is ¨OH, Z1 is ¨OH, Z2 is ¨H, Z3 is ¨H, Ar2 is benzoimidazolyl, wherein at
least one of
R8 or R9 is not ¨H.
In another embodiment, R1 is ¨halo, R4 is ¨halo, Ari is
J is ¨OH, Z1 is ¨CH2OH, Z2 is ¨H, Z3 is ¨H, At-) is benzoimidazolyl, wherein
at least
one of R8 or R9 is not ¨H.
In another embodiment, R1 is ¨halo, R4 is ¨halo, Ari is,
J is ¨OH, Z1 is ¨OH, Z2 is ¨H, Z3 is ¨H, Ar2 is phenyl, wherein s is 1.
In another embodiment, R1 is ¨halo, R4 is ¨halo, Ari is
Ri
J is ¨OH, Z1 is ¨CH2OH, Z2 is ¨H, Z3 is ¨H, Ar2 is phenyl, wherein s is 2.
In another embodiment, the dashed line is a double bond, R1 is ¨halo, Ari is
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J is ¨OH, Z1 is ¨OH, Z? is ¨H, and Z3 IS ¨H.
In another embodiment, the dashed line is a double bond, R1 is ¨halo, Ari is
J is ¨OH, Zi is ¨CFLOH, Z7 is ¨H, and Z3 is ¨H.
In another embodiment, the dashed line is a double bond, R1 is ¨halo, An is
R1
J is ¨OH, Z1 is ¨OH, 12 is ¨H, Z3 is ¨H, An2 is benzooxazolyl, wherein at
least one of R8
or R9 is not ¨H.
In another embodiment, the dashed line is a double bond, R1 is ¨halo, An is
J is ¨OH, Z1 is ¨CH2OH, Z2 is ¨H, Z3 is ¨H, Ar2 is benzooxazolyl, wherein at
least one
of R8 or R9 is not ¨H.
In another embodiment, the dashed line is a double bond, R1 is ¨halo, Art is
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J is ¨OH, Z1 is ¨OH, Z., is ¨H, Z3 is ¨H, Ar> is benzothiazolyl, wherein at
least one of R8
or R9 is not ¨H.
In another embodiment, the dashed line is a double bond, R1 is ¨halo, An is
Q
Rir.,N
,
J is ¨OH, Z1 is ¨CH2OH, Z2 is ¨H, Z3 is ¨H, Ar2 is benzothiazolyl, wherein at
least one
of R8 or R9 is not ¨H.
In another embodiment, the dashed line is a double bond, R1 is ¨halo, Ari is
Q
\1
Ri
,
J is ¨OH, Z1 is ¨OH, Z2 is ¨H, Z3 is ¨H, Ar-) is benzoimidazolyl, wherein at
least one of
R8 or R9 is not ¨H.
In another embodiment, the dashed line is a double bond, R1 is ¨halo, An is
Q
Ri
,
J is ¨OH, Z1 is ¨CH,OH, Z2 is ¨H, Z3 is ¨H, Ar, is benzoimidazolyl, wherein at
least
one of R8 or R9 is not ¨H.
In another embodiment, the dashed line is a double bond, R1 is ¨halo, An is
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J is ¨OH, Zi is ¨OH, Z, is ¨H, Z3 is ¨H, Ar2 is phenyl, wherein s is 1.
In another embodiment, the dashed line is a double bond, R1 is ¨halo, An is
5
Ri
J is ¨OH, Z1 is ¨OH, Z2 is ¨H, Z3 is ¨H, Ar2 is phenyl, wherein s is 2.
In another embodiment, the dashed line is a double bond, R1 is ¨halo, Ari is
Ri
J is ¨OH, Z1 is ¨CH,OH, Z2 is ¨H, Z3 is ¨H, Ar2 is phenyl, wherein s is 1.
In another embodiment, the dashed line is a double bond, R1 is ¨halo, Ari is
J is ¨OH, Zi is ¨CH,OH, Z2 is ¨H, Z3 is ¨H, Ar2 is phenyl, wherein s is 2.
In another embodiment, the dashed line is a double bond, R1 is ¨halo, Ari is
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J is ¨OH, Z1 is ¨OH, Z2 is ¨H, Z3 is ¨H, Ar2 is phenyl, wherein s is 1, and
R14 is -(C1-
C6)alkyl, ¨halo, -C(halo)3, -0C(halo)3, -OR7, -N(R7)2, -S02R7, or -
S02C(hal0)3.
In another embodiment, the dashed line is a double bond, R1 is ¨halo, An is
J is ¨OH, Z1 is ¨CH2OH, Z7 is ¨H, Z3 is ¨H, Ar2 is phenyl, wherein s is 1, and
R14 is -(CI-C6)alkyl, ¨halo, -C(halo)3, -0C(halo)3, -0R7, -N(R7)2, -S02R7, or
-S02C(halo)3.
In another embodiment, the dashed line is a double bond, R1 is ¨halo, Ari is
R1
J is ¨OH, Zi is ¨OH, Z2 is ¨H, Z3 is ¨H, Ar2 is phenyl, wherein s is 2, and
each R14 is
independently -(CI-C6)alkyl, ¨halo, -C(halo)3, -0C(halo)3, -0R7, -N(R7)2, -
SO2R7, or
-S02C(halo)3.
In another embodiment, the dashed line is a double bond, R1 is ¨halo, An is
Ri
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J is ¨OH, Z1 is ¨CH2OH, Z7 is ¨H, Z3 is ¨H, Ar7 is phenyl, wherein s is 2, and
each R14
is independently -(C1-C6)alkyl, ¨halo, -C(halo)3, -0C(halo)3, -0R7, -N(R7)2, -
S02R7, or
-S02C(halo)3.
In another embodiment Q is
..õõõ
wherein the compound of formula II is racemic.
In another embodiment Q is
HO-OH HO,,OH
and VW,"
wherein the % ee of the R enantiomer is greater than 60%.
In another embodiment Q is
OH HO,õ.OH
and
wherein the % ee of the R enantiomer is greater than 70%.
In another embodiment Q is
OH HO,õ .OH
and
wherein the % ee of the R enantiomer is greater than 80%.
In another embodiment Q is
HOOH HO,õ.OH
N/VV, and %NV,
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wherein the % ee of the R enantiomer is greater than 90%.
In another embodiment Q is
HOOH HO,õ, OH
--, and
wherein the % ee of the R enantiomer is greater than 99%.
In another embodiment Q is
HO¨ HO,,,OH
---õ and
wherein the % ee of the S enantiomer is greater than 60%.
In another embodiment Q is
HO.OH HO,õ, OH
WY, and
wherein the % ee of the S enantiomer is greater than 70%.
In another embodiment Q is
HO.õõ...,-----..,
OH
WV, and
wherein the % ee of the S enantiomer is greater than 80%.
In another embodiment Q is
HOOH HO,,
OH
and
wherein the % ee of the S enantiomer is greater than 90%.
In another embodiment Q is
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HO,õ' OH
and ¨
wherein the % ee of the S enantiomer is greater than 99%.
In another embodiment Q is
OH
In another embodiment Q is
HOE,'OH
In another embodiment, the invention encompasses compounds formula 11.4:
Ari. ,R4
W_
(R3)m
R20
1\r
Ar2
(11.4)
or a pharmaceutically acceptable salt thereof, where the dashed line, W, X,
Ark Ar2, R3,
R4, R20, and m are as defined above for compounds of formula 1.4,
wherein Q is
Zixl\¨z3
Z2 Z3
Zi is -OH, -SH, N(R20)2, -CH2-0H, -CH,)-SH, or -CH2-N(R20)2;
Z, is ¨H or -CH3;
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each Z3 is independently -H or -CH3; and
J is -OH, -SH, or -N(R20)2.
In another embodiment, the invention encompasses compounds formula 11.3:
Ari. ..R4
(R3)rn
R20
5 Ar2
(II.3)
or a pharmaceutically acceptable salt thereof, where the dashed line, W, X,
Ari, Ar2, R3)
R4, R10, and m are as defined above for compounds of formula 1.3,
10 wherein Q is
Zi).717z3
Z2 Z3
Z1 is -OH, -SH, NOZ20)2, -CH7-0H, -CH2-SH, or -CH2-N(R70)2;
1, is -H or -CH3;
15 each Z3 is independently -H or -CH3; and
J is -OH, -SH, or -N(R20)2.
In another embodiment, the invention encompasses compounds formula 11.2:
X>N
¨(R36
R20
Ar2
20 (11.2)
or a pharmaceutically acceptable salt thereof, where the dashed line, W, X,
Art, Ar2, R3,
R4, R70, and m are as defined above for compounds of formula 1.2,
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wherein Q is
Zi
Z2 Z3
Z1 is -OH, -SH, N(R20)2, -CH2-OH, -CH2-SH, or -CH2-N(R202;
5 Z2 1S ¨H or -CH3;
each Z3 is independently ¨H or ¨CH3; and
J is -OH, -SH, or -N(R20)2=
In another embodiment, the invention encompasses compounds formula II.1:
AriõR4
X R20
i\r
Ar2
or a pharmaceutically acceptable salt thereof, where the dashed line, W, X,
Art, Ar2, R35
R45 R20, and m are defined above for compounds of formula 1.1,
wherein Q is
Ziz3
Z( 23
5
Z1 is -OH, -SH, N(R20)2, -CH2-0H, -CH2-SH, or -CH2-N(R20)2;
12 is ¨H or -CH3;
each Z3 is independently ¨H or ¨CH3; and
J is -OH, -SH, or -N(R20)2.
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5.3 COMPOUNDS OF FORMULA III
Preferred compounds of formula II are compounds of formula III:
Ari. .R4
)¨(R3)rn
,H
X N
Ar2
(III)
or a pharmaceutically acceptable derivative thereof, where the dashed line, W,
X, R3, R4,
and m are as defined above for compounds of formula I,
wherein Ari is:
HO
OH
I
Ri N
R1 is ¨Cl, -F, or ¨CF3;
wherein Ar2 is:
JVV, JYVVN
aVVV,
JVVV% JN.ANN JVV1l,
10 1101
NNS
CF3 R14 R14'
R14 ' R14' , CF3 0
= F3C,..-S02 CF3 or
C.c 3 R8 R9
R14 is ¨H, -Cl, -F, -Br, -0CF3, -(C1-C6)alkyl, -SO2CF3, -S02(C1-C6)alkyl,
-OCH3, -OCH2CH3, or -OCH(CH3)2, and preferably is -CF3, -0CF3, -Cl, or ¨F;
R14. IS ¨H, ¨Cl, -F, Br, -CH3, -CH2CH3, -OCH3, -0CF3, or ¨OCH2CH3; and
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each R8 and R9 is independently -H, -CI, -Br, -F, -CH3, -OCH3, -OCH2CH3,
-CF3, -0CF3, iso-propyl, or tert-butyl.
In addition to being highly soluble in aqueous solution at both pH 6.8 and pH
1.2, having a very high therapeutic index, and having excellent
phannacokinetic
parameters as described for formulae I and II, compounds of formula III are
preferred
because they are also very bioavailable, and are believed to be highly
efficacious in
animals for the treatment of pain. Bioavailability is a measure of how much of
the dose
administered reaches systemic circulation after oral administration. For
example,
compounds of formula III R6 and GI are 68.9% and 70.7% bioavailable following
oral
administration, respectively. The compound of formula III D2 produced a 78.7%
maximum reversal of FCA-induced hyperalgesia at 5 hours post-administration,
with an
ED50 of 1.63 mg/kg.
Certain embodiments of formula III are presented below.
In one embodiment, a compound of formula III is a pharmaceutically acceptable
derivative of a compound of formula III.
In another embodiment, a compound of formula I is a compound of formula III
whererein the derivative is a pharmaceutically acceptable salt.
In another embodiment, a compound of formula III is a pharmaceutically
acceptable salt of a compound of formula III.
In another embodiment, Ari is:
HO
OH
In a preferred embodiment, Ari is:
HOE,f OH
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In another embodiment, m is 2.
In another embodiment, two R3 groups together form a (C7-C6)bridge, which is
unsubstituted or substituted with 1, 2 or 3 independently selected R8 groups,
and which
bridge optionally contains -HC=CH- within the (C7-C6)bridge.
In another embodiment, two R3 groups together form a (C7-C6)bridge, which is
unsubstituted or substituted with an R8 group, and which bridge optionally
contains
-HC=CH- within the (C7-C6)bridge.
In another embodiment, two R3 groups together form a (C7-C3)bridge, which is
unsubstituted or substituted with an R8 group, and which bridge optionally
contains
-HC=CH- within the (C7-C3)bridge.
In another embodiment, two R3 groups together form a (C7-C3)bridge, which is
unsubstituted and which bridge optionally contains -HC=CH- within the (C7-
C3)bridge.
In another embodiment, two R3 groups together form a (C2)bridge, a -HC=CH-
bridge, or a (C3)bridge each of which is unsubstituted.
In another embodiment, two R3 groups together form a (C2-C6)bridge, which is
unsubstituted or substituted with 1, 2 or 3 independently selected R8 groups,
which
bridge optionally contains -HC=CH- within the (C7-C6)bridge, and which bridge
joins
positions 2 and 6 of the piperidine, 1,2,3,6-tetrahydropyridine or piperazine
ring.
In another embodiment, two R3 groups together form a (C7-C6)bridge, which is
unsubstituted or substituted with an R8 group, which bridge optionally
contains
-HC=CH- within the (C2-C6)bridge, and which bridge joins positions 2 and 6 of
the
piperidine, 1,2,3,6-tetrahydropyridine or piperazine ring.
In another embodiment, two R3 groups together form a (C7-C3)bridge, which is
unsubstituted or substituted with an R8 group, which bridge optionally
contains
-HC=CH- within the (C7-C3)bridge, and which bridge joins positions 2 and 6 of
the
piperidine, 1,2,3,6-tetrahydropyridine or piperazine ring.
In another embodiment, two R3 groups together form a (C7-C3)bridge, which is
unsubstituted, which bridge optionally contains -HC=CH- within the (C2-
C3)bridge, and
which bridge joins positions 2 and 6 of the piperidine, 1,2,3,6-
tetrahydropyridine or
piperazine ring.
In another embodiment, two R3 groups together form a (C2)bridge, a -HC=CH-
bridge, or a (C3)bridge each of which is unsubstituted, and which bridge joins
positions
2 and 6 of the piperidine, 1,2,3,6-tetrahydropyridine or piperazine ring.
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In another embodiment, two R3 groups together form a -CH2-N(Ra)-CH2- bridge
(B1), a
Rb Rb
0=0 0=s=0
-CH2 -N-CH2 - bridge (B2), or a -CH2 -N-CH2 - bridge (B3);
5
wherein Ra is selected from -H, -(Ci-C6)alkyl, -(C3-C8)cycloalkyl, -CH2-C(0)-
R,, -(CH2)-C(0)-0Rc, -(CH2)-C(0)-N(Rc)2, -(CH2)2-0-R,, -(CH2)2-S(0)2-N(Rc)2,
or
-(CF12)2-N(R)S(0).2-R;
Rb is selected from:
10 (a) -H, -(C1-C6)alkyl, -(C3-C8)cycloalkyl, -(3- to 7-
membered)heterocycle, -N(R)2, -N(Rc(C3-C8)cycloalkyl, or -N(R,)-(3- to 7-
membered)heterocycle; or
(b) ¨phenyl, -(5- or 6-membered)heteroaryl, -N(R)-phenyl, or
to 10-membered)heteroaryl, each of which is unsubstituted or substituted with
1,2 or 3
15 independently selected R7 groups; and
each Rc is independently selected from -H or -(C1-C4)alkyl;
In another embodiment, the BI, B2, or B3 bridge joins positions 2 and 6 of the
piperidine, 1,2,3,6-tetrahydropyridine or piperazine ring.
In another embodiment, two R3 groups form a bicyclo group to give one of the
20 following structures,
Ariõ R4 Ari. -R4
(N) or
X
,
X NH
Ar2 Ar2
In another embodiment, in is I.
25 In another embodiment, m is 0.
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In another embodiment X is 0.
In another embodiment the dashed line denotes the presence of a bond and R4 is
absent.
In another embodiment W is N and R4 is absent.
In another embodiment R4 is -H, -OH, -Cl, or F.
In another embodiment, each R70 is independently -H or -(C1-C6)alkyl.
In another embodiment, each R10 is ¨H.
In another embodiment, each R20 is -(C1-C6)alkyl.
In another embodiment Ar, is selected from
./SANN
../NANN ./vIAA
el el
NS
R14' D "14'
=
R14 ' CF3 0
F3C
õ-S02 CF 3 or 40
CF3
R8 R9
In another embodiment An is
HOcOH
Ri N
wherein the compound of formula III is racemic.
In another embodiment Ari is
HOOH
OH
I N
Ri Ri N
and
wherein the % ee of the R enantiomer is greater than 60%.
In another embodiment Art is
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OH HO,õ.
OH
NI N
Ri Ri
and
wherein the % ee of the R enantiomer is greater than 70%.
In another embodiment Ari is
HO HO,HO,õ.0H
I NI N
Ri Ri
and
wherein the % ee of the R enantiomer is greater than 80%.
In another embodiment Art is
HOOH HOOH
I NI N
Ri Ri
and
wherein the % ee of the R enantiomer is greater than 90%.
In another embodiment Ari is
HO OH HO,,,rOH
N
Ri Ri N
and
wherein the % ee of the R enantiomer is greater than 99%.
In another embodiment An is
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HOOH HO,õ .OH
NI N
Ri Ri
and
wherein the % ee of the S enantiomer is greater than 60%.
In another embodiment Ari is
HO HO,HO,õ.OH
I NI N
Ri Ri
and
wherein the % ee of the S enantiomer is greater than 70%.
In another embodiment Ari is
HO HO,HO,õ.OH
N
Ri Ri N
and
wherein the % ee of the S enantiomer is greater than 80%.
In another embodiment Art is
HO HO,,HO,õ.OH
I NI N
Ri Ri
and
wherein the % ee of the S enantiomer is greater than 90%.
In another embodiment Ari is
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HO
OH OH
/1
Ri N
and
wherein the % ee of the S enantiomer is greater than 99%.
In another embodiment Ari is
HO
OH
Ri N
In another embodiment Ari is
OH
N
R
i
In another embodiment the compound of formula III is
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OH
H04,,
N
CI
0 NH
R,4
or a pharmaceutically acceptable derivative thereof, where R14 is as defined
above for
the compounds of formula I.
5 In another embodiment the compound of formula III is
OH
N/
ONH
R14
or a pharmaceutically acceptable derivative thereof, where R14 is as defined
above for
10 the compounds of formula I.
In another embodiment the compound of formula III is
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OH
N
CI
O NH
1401
R14
or a pharmaceutically acceptable derivative thereof, where R14 is as defined
above for
the compounds of formula I.
In another embodiment the compound of formula III is
OH
1-104,
N
N
NH
1401
R14
or a pharmaceutically acceptable derivative thereof, where R14 is as defined
above for
the compounds of formula I.
In another embodiment the compound of formula III is
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OH
N
CI
0 NH
CF
R"
or a pharmaceutically acceptable derivative thereof, where R14 is as defined
above for
the compounds of formula I.
In another embodiment the compound of formula III is
OH
N
NH
0
CF
R"
or a pharmaceutically acceptable derivative thereof where R14 is as defined
above for
the compounds of formula I.
In another embodiment the compound of formula III is
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OH
N
CI
O NH
1401 CF,
R14
or a pharmaceutically acceptable derivative thereof, where R14 is as defined
above for
the compounds of formula I.
In another embodiment the compound of formula III is
OH
HO,
NH
N
1401 CF3
or a pharmaceutically acceptable derivative thereof, where R14 is as defined
above for
the compounds of formula I.
In another embodiment the compound of formula III is
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OH
H0,4õ
N
CI
N
0 NH
=)N
y,
CF,
or a pharmaceutically acceptable derivative thereof, where R14 is as defined
above for
the compounds of formula I.
In another embodiment the compound of formula III is
OH
N
0 NH
i4
CF3
or a pharmaceutically acceptable derivative thereof, where R14 is as defined
above for
the compounds of formula I.
In another embodiment the compound of formula III is
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OH
HO,
N
CI
N
NH
0
1401 R"
CF,
or a pharmaceutically acceptable derivative thereof, where R14 is as defined
above for
the compounds of formula I.
In another embodiment the compound of formula III is
OH
HOõ,
N
0 NH
140 R,4
CF
or a pharmaceutically acceptable derivative thereof, where R14 is as defined
above for
the compounds of formula I.
In another embodiment the compound of formula III is
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OH
N
CI
N
0 NH
N
=r"
OC F3
or a pharmaceutically acceptable derivative thereof, where R14 is as defined
above for
the compounds of formula I.
In another embodiment the compound of formula III is
OH
HO,
N
0 NH
14
OCF3
or a pharmaceutically acceptable derivative thereof, where R14 is as defined
above for
l 0 the compounds of formula I.
In another embodiment the compound of formula III is
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OH
H0,4õ
CI
N
ONH
R"
OC F3
or a pharmaceutically acceptable derivative thereof, where R14 is as defined
above for
the compounds of formula I.
In another embodiment the compound of formula III is
OH
N
N
NH
1401 R"
OCF 3
or a pharmaceutically acceptable derivative thereof, where R14 is as defined
above for
the compounds of formula I.
In another embodiment the compound of formula III is
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OH
H0,4,
N
CI
O NH
JN
R,.
or a pharmaceutically acceptable derivative thereof, where R14 is as defined
above for
the compounds of formula I.
In another embodiment the compound of formula III is
OH
HO,,
N
O
NH
R,.
or a pharmaceutically acceptable derivative thereof, where R14 is as defined
above for
the compounds of formula I.
In another embodiment the compound of formula III is
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OH
HO,
N
CI
N
0 NH
1401
or a pharmaceutically acceptable derivative thereof, where R14 is as defined
above for
the compounds of formula I.
In another embodiment the compound of formula III is
OH
N
N
0 NH
R "
or a pharmaceutically acceptable derivative thereof, where R14 is as defined
above for
the compounds of formula I.
In another embodiment the compound of formula III is
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OH
N
CI
0 NH
)CF,
R"
or a pharmaceutically acceptable derivative thereof, where R14 is as defined
above for
the compounds of formula I.
In another embodiment the compound of formula III is
OH
N
0 NH
CF
or a pharmaceutically acceptable derivative thereof, where R14 is as defined
above for
the compounds of formula I.
In another embodiment the compound of formula III is
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OH
HO,
N
CI
0NH
CF 3
R
or a pharmaceutically acceptable derivative thereof, where R14 is as defined
above for
the compounds of formula I.
In another embodiment the compound of formula III is
OH
N
N
O NH
CF3
Rt4
or a pharmaceutically acceptable derivative thereof, where R14 is as defined
above for
the compounds of formula I.
In another embodiment the compound of formula III is
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OH
N
CI
ONH
CF3
or a pharmaceutically acceptable derivative thereof, where R14 is as defined
above for
the compounds of formula I.
In another embodiment the compound of formula III is
OH
N
0 NH
CF3
or a pharmaceutically acceptable derivative thereof, where R14 is as defined
above for
the compounds of formula I.
In another embodiment the compound of formula III is
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OH
N
CI
0 NH
1401 Ri4
CF3
or a pharmaceutically acceptable derivative thereof, where R14 is as defined
above for
the compounds of formula I.
In another embodiment the compound of formula III is
OH
N
N
0 NH
1401 Ri,
CF3
or a pharmaceutically acceptable derivative thereof, where R14 is as defined
above for
the compounds of formula I.
In another embodiment the compound of formula III is
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OH
N
CI
ONH
Ri4
OCF3
or a pharmaceutically acceptable derivative thereof, where R14 is as defined
above for
the compounds of formula I.
In another embodiment the compound of formula III is
OH
N
N
0 NH
RI4
OCF3
or a pharmaceutically acceptable derivative thereof, where R14 is as defined
above for
the compounds of formula I.
In another embodiment the compound of formula III is
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OH
N
CI
N
0-"NH
1401
OCF3
or a pharmaceutically acceptable derivative thereof, where R14 is as defined
above for
the compounds of formula I.
In another embodiment the compound of formula III is
OH
N
O
N
NH
1401 12,4
OCF3
or a pharmaceutically acceptable derivative thereof, where R14 is as defined
above for
the compounds of formula I.
In another embodiment the compound of formula III is
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OH
H0,4NH
CI
R
or a pharmaceutically acceptable derivative thereof, where R14 is as defined
above for
the compounds of formula I.
In another embodiment the compound of formula III is
OH
H0,44
NH
N
Ri4
or a pharmaceutically acceptable derivative thereof, where R14 is as defined
above for
the compounds of formula I.
In another embodiment the compound of formula III is
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OH
HO,,,,
\,
I
N
N
0 NH
401
Ri4
or a pharmaceutically acceptable derivative thereof, where R14 is as defined
above for
the compounds of formula I.
In another embodiment the compound of formula III is
OH
HOõ
...õ,..
I
F
N
0' NH
1401
R"
or a pharmaceutically acceptable derivative thereof, where R14 is as defined
above for
the compounds of formula I.
In another embodiment the compound of formula III is
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OH
N
ONH
=)N
CF
or a pharmaceutically acceptable derivative thereof, where R14 is as defined
above for
the compounds of formula I.
In another embodiment the compound of formula III is
OH
HOõ,,
ONH
I
CF
or a pharmaceutically acceptable derivative thereof, where R14 is as defined
above for
the compounds of formula I.
In another embodiment the compound of formula III is
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OH
CI N
0 NH
1401 CF,
R"
or a pharmaceutically acceptable derivative thereof, where R14 is as defined
above for
the compounds of formula I.
In another embodiment the compound of formula III is
OH
0 NH
111 CF3
RI4
or a pharmaceutically acceptable derivative thereof, where R14 is as defined
above for
the compounds of formula I.
In another embodiment the compound of formula III is
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OH
C1,...õ..-ly
,.....õ N,.......,
N
0 NH
N
I
ys-- 14
R
CF3
or a pharmaceutically acceptable derivative thereof, where R14 is as defined
above for
the compounds of formula I.
In another embodiment the compound of formula III is
OH
HO,
õ,....õ
1
...õ,,,y,N
F
....õõNõ......,
N
NH
0
i
=N
I
,,
R
CF3
or a pharmaceutically acceptable derivative thereof, where R14 is as defined
above for
the compounds of formula I.
In another embodiment the compound of formula III is
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OH
NH
0
1401 N1,
CF,
or a pharmaceutically acceptable derivative thereof, where R14 is as defined
above for
the compounds of formula I.
In another embodiment the compound of formula III is
OH
N
NH
0
1401 R"
CF,
or a pharmaceutically acceptable derivative thereof, where R14 is as defined
above for
the compounds of formula I.
In another embodiment the compound of formula III is
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OH
N
ONH
OCF3
or a pharmaceutically acceptable derivative thereof, where R14 is as defined
above for
the compounds of formula I.
In another embodiment the compound of formula III is
OH
NH
0
OCF3
or a pharmaceutically acceptable derivative thereof, where R14 is as defined
above for
the compounds of formula I.
In another embodiment the compound of formula III is
=
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OH
HO
CI Nj
ONH
1401
OCF,
or a pharmaceutically acceptable derivative thereof, where R14 is as defined
above for
the compounds of formula I.
In another embodiment the compound of formula III is
OH
HO,
N
O
NH
OCF3
or a pharmaceutically acceptable derivative thereof, where R14 is as defined
above for
the compounds of formula I.
In another embodiment, the invention encompasses compounds of formula 111.4:
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,R4
(R36
X N,H
Ar2
(1II.4)
or a pharmaceutically acceptable salt thereof, where the dashed line, W, X,
Ark Ar2, R31
R4, and m are as defined above for compounds of formula 1.4,
wherein Ari is:
HO
OH
/1
I
Ri N
R1 is ¨Cl, -F, or ¨CF3;
wherein Ar2 is:
JVNAA JNAnn
= F 1101 D X N NS
I
R14' "14'
R14' F F 0 õ.S02 or
FF F CF3 41
FF F ' F3C
R9 ,
R14 is ¨H, ¨Cl, -F, -Br, -CH3, -CH2CH3, -OCH3, or ¨OCH2CH3;
R9 is ¨Cl, F, or CH3.
In another embodiment, the invention encompasses compounds of formula 111.3:
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Ari, ,R4
W
/
N) (R3)m
,H
X N
1
Ar2
(111.3)
or a pharmaceutically acceptable salt thereof, where the dashed line, W, X,
Ari, Ar2, R.3,
R4, and m are as defined above for compounds of formula 1.3,
wherein Ari is:
HO
OH
I
Ri N
,
R1 is ¨CI, -F, or ¨CF3;
wherein Ar2 is:
ISI y ISI
1401 NS
R14 R14 N
0 .
FF F , \
CF3 ' Eil\F ' F3C02 or
F
R9,
R14 is ¨Cl, -F, -CH3, -CH2CH3, -OCH3, or ¨OCH2CH3;
R9 is ¨Cl, F, or CH3.
Illustrative compounds of formula III are listed below in Tables 1-30:
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Table 1
OH
N
ONH
FF c
(IIIa)
and pharmaceutically acceptable derivatives thereof, where:
Compound R1 R14
AAA -CI -Cl
AAB -CI -F
AAC -CI -OCH3
AAD -Cl -OCH2CH3
AAE -F -CI
AAF -F -F
AAG -F -OCH3
AAH -F -OCH2CH3
AAI -CF3 -Cl
AAJ -CF3 -F
AAK -CF3 -OCH3
AAL -CF3 -OCH2CH3
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Table 2
OH,
OH
N
Ri
ONH
.,14*
FE c
(IIIb)
and pharmaceutically acceptable derivatives thereof, where:
Compound R R14-
AAM -Cl -Cl
AAN -Cl -F
AA0 -Cl -OCH3
AAP -Cl -OCH2CH3
AAQ -F -Cl
AAR -F -F
AAS -F -OCH3
AAT -F -OCH2CH3
AAU -CF3 -Cl
AAV -CF3 -F
AAW -CF3 -OCH3
AAX -CF3 -OCH2CH3
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Table 3
OH,
0 NH
R1 4'
FF F
(IIIc)
and pharmaceutically acceptable derivatives thereof, where:
Compound R1 R14.
AAY -Cl -Cl
AAZ -Cl -F
ABA -Cl -OCH3
ABB -C1 -OCH2CH3
ABC -F -Cl
ABD -F -F
ABE -F -OCH3
ABF -F -OCH2CH3
ABG -CF3 -C1
ABH -CF3 -F
ABI -CF3 -OCH3
ABJ -CF3 -OCH2CH3
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Table 4
OH
OH
\
N
R1
0NH
FF F
(II
Id)
and pharmaceutically acceptable derivatives thereof, where:
Compound RI R14'
ABK -CI -Cl
ABL -Cl -F
ABM -CI -OCH3
ABN -Cl -OCH2CH3
ABO -F -Cl
ABP -F -F
ABQ -F -OCH3
ABR -OCH2CH3
ABS -CF3 -Cl
ABT -CF3 -F
ABU -CF3 -OCH3
ABV -CF3 -OCH2CH3
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Table 5
OH
OH
N
0NH
R14.
FF F
(tile)
and pharmaceutically acceptable derivatives thereof, where:
Compound R1 R14
ABW -Cl -Cl
ABX -Cl -F
ABY -Cl -OCH3
ABZ -Cl -OCH2CH3
ACA -F -Cl
ACB -F -F
ACC -F -OCH3
ACD -F -OCR2CH3
ACE -CF3 -Cl
ACF -CF3 -F
ACG -CF3 -OCH3
ACH -CF3 -OCH2CH3
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Table 6
OH
XOH
\N/
0NH
R 4 '
FF c
('III)
and pharmaceutically acceptable derivatives thereof, where:
Compound RI R14.
AC! -Cl -Cl
ACJ -Cl -F
ACK -Cl -OCH3
ACL -Cl -OCH2CH3
ACM -F -Cl
ACN -F -F
ACO -F -OCH3
ACP -F -OCH2CH3
ACQ -CF3 -Cl
ACR -CF3 -F
ACS -CF3 -OCH3
ACT -CF3 -OCH2CH3
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Table 7
OH,õ,,
OH
N
R1
0 NH
R14'
0\
CF3
(Mg)
and pharmaceutically acceptable derivatives thereof, where:
Compound R1 R14
BAA -CI -CH3
BAB -Cl -CH2CH3
BAC -Cl -Cl
BAD -F -CH3
BAE -F -CH2CH3
BAF -F -CI
BAG -CF3 -CH3
BAH -CF3 -CH2CH3
BAI -CF3 -Cl
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Table 8
OH,
OH
N
Ri
ONH
R14.
0\
CF3
(Mb)
and pharmaceutically acceptable derivatives thereof, where:
Compound R1 R14.
BAJ -Cl -CH3
BAK -Cl -CH2CH3
BAL -Cl -Cl
BAM -F -CH3
BAN -F -CH2CH3
BAO -F -Cl
BAP -CF3 -CH3
BAQ -CF3 -CH2CH3
BAR -CF3 -Cl
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Table 9
OH,
'COH
N/
0NH
0\
CF3
and pharmaceutically acceptable derivatives thereof, where:
Compound R1 R14
BAS -Cl -CH3
BAT -Cl -CH2CH3
BAU -Cl -Cl
BAV -F -CH3
BAW -F -CH2CH3
BAX -F -Cl
BAY -CF3 -CH3
BAZ -CF3 -CH2CH3
BBA -CF3 -Cl
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Table 10
OH
OH
N
Ri
ONH
401 D
.µ14'
0\
CF3
(IIIj)
and pharmaceutically acceptable derivatives thereof, where:
Compound R1 R14
BBB -Cl -CH3
BBC -Cl -CH2CH3
BBD -Cl -Cl
BBE -F -CH3
BBF -F -CH2CH3
BBG -F -Cl
BBH -CF3 -CH3
BBI -CF3 -CH2CH3
BBJ -CF3 -Cl
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Table 11
OH
OH
N
0NH
IND
14
0\
CF3
(IIIk)
and pharmaceutically acceptable derivatives thereof, where:
Compound RI Ri4.
BBK -Cl -CH3
BBL -Cl -CH2CH3
BBM -Cl -Cl
BBN -F -CH3
BBO -F -CH2CH3
BBP -F -CI
BBQ -CF3 -CH3
BBR -CF3 -CH2CH3
BBS -CF3 -Cl
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Table 12
OH
)0H
R(YN
0NH
el R1
0\
CF3
OHO
and pharmaceutically acceptable derivatives thereof, where:
Compound R1 Ri4=
BBT -Cl -CH3
BBU -Cl -CH2CH3
BBV -Cl -CI
BBW -F -CH3
BBX -F -CH2CH3
BBY -F -Cl
BBZ -CF3 -CH3
BCA -CF3 -CH2CH3
BCB -CF3 -Cl
In other embodiments, substituent R14. of Tables 1-12 can be H.
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Table 13
OH
N
Ri
0 NH
F
and pharmaceutically acceptable derivatives thereof, where:
Compound R1
CAA -Cl
CAB -F
CAC -CF3
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Table 14
OF
OH
7N
R1
0NH
JN
F c
F F
(IIIn)
and pharmaceutically acceptable derivatives thereof, where:
Compound R1
CAD -Cl
CAE -F
CAF -CF3
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Table 15
OH,
RrN
0NH
F
(MO
and pharmaceutically acceptable derivatives thereof, where:
Compound R1
CAG -Cl
CAH -F
CAI -CF3
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Table 16
OH
OH
N
Ri
ONH
F-71\ c
F F
('lip)
and pharmaceutically acceptable derivatives thereof, where:
Compound R1
CAJ -Cl
CAK -F
CAL -CF3
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Table 17
OH
OH
I
N
R1
0NH
F c
F r
(IIIq)
and pharmaceutically acceptable derivatives thereof, where:
Compound R1
CAM -Cl
CAN -F
CAO -CF3
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Table 18
OH
,COH
RN
0NH
F-11\c
F
(IIIr)
and pharmaceutically acceptable derivatives thereof, where:
Compound R1
CAP -Cl
CAQ -F
CAR -CF3
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Table 19
OH
N
Ri
0NH
4111
-SO2
r 3t,
(Ills)
and pharmaceutically acceptable derivatives thereof, where:
Compound R1
DAA -Cl
DAB -F
DAC -CF3
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Table 20
OH
N
Ri
ONH
F3CS02
(lilt)
and pharmaceutically acceptable derivatives thereof, where:
Compound R1
DAD -Cl
DAE -F
DAF -CF3
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Table 21
OH,
'COH
N
1=2;
ONH
-SO2
3...r,
OHO
and pharmaceutically acceptable derivatives thereof, where:
Compound R
DAG -Cl
DAH -F
DAI -CF3
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Table 22
OH
OH
I
N
R1
F
N/
0 NH
S
-SO2
F3C
(IIv)
and pharmaceutically acceptable derivatives thereof, where:
Compound R 1
DAJ -Cl
DAK -F
DAL -CF3
,
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Table 23
OH
OH
N
Ri
ONH
,S02
F3C
(IIIw)
and pharmaceutically acceptable derivatives thereof, where:
Compound R1
DAM -Cl
DAN -F
DA0 -CF3
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Table 24
OH
OH
0NH
1.1
-SO2
F3C
(Ilx)
and pharmaceutically acceptable derivatives thereof, where:
Compound R1
DAP -CI
DAQ -F
DAR -CF3
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Table 25
OH,
OH
I
N
0NH
NS
R9
(Illy)
and pharmaceutically acceptable derivatives thereof, where:
Compound R1 R9
EAA -Cl -Cl
EAB -Cl -F
EAC -Cl -CH3
EAD -F -Cl
EAE -F -F
EAF -F -CH3
EAG -CF3 -Cl
EAH -CF3 -F
EAI -CF3 -CH3
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Table 26
OH,,,,.
OH
N
R1
0 NH
NS
R9
(1hk)
and pharmaceutically acceptable derivatives thereof, where:
Compound R1 R9
EAJ -Cl -Cl
EAK -Cl -F
EAL -Cl -CH3
EAM -F -CI
EAN -F -F
EAO -F -CH3
EAP -CF3 -Cl
EAQ -CF3 -F
EAR -CF3 -CH3
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Table 27
OH,
'COH
f)1-1
i \
\
1 I
RN Rry N
N N
/ \
/ \
\ N/ N CH3
0NH 0NH
NS )N,
N ' S
4. .
R
R8 R9 8 R9
or
(IIIaa) (IIIab)
and pharmaceutically acceptable derivatives thereof, where:
Compound RI R8 Ry
EAS1 aa or ab -Cl -H -H
EAS2 aa or ab -Cl -H -Cl
EAS3 aa or ab -Cl -H -Br
EAS4 aa or ab -Cl -H -F
EAS5 aa or ab -Cl -H -CH3
EAS6 aa or ab -Cl -H -OCH3
EAS7 aa or ab -Cl -H -OCH2CH3
EAS8 aa or ab -Cl -H -CF3
EAS9 aa or ab -Cl -H -0CF3
EASIO aa or ab -Cl -H iso-propyl
EASII aa or ab -Cl -H tert-butyl
EAS12 aa or ab -Cl -Cl -H
EAS13 aa or ab -Cl -Cl -Cl
EASI4 aa or ab -Cl -Cl -Br
EASI5 aa or ab -Cl -Cl -F
EAS16 aa or ab -Cl -Cl -CH3
EAS17 aa or ab -Cl -Cl -OCH3
EAS18 aa or ab -Cl -Cl -OCH2CH3
EAS19 aa or ab -Cl -Cl -CF3
EAS20 aa or ab -Cl -CI -0CF3
EAS21 aa or ab -Cl -Cl iso-propyl
EAS22 aa or ab -Cl -CI tert-butyl
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Compound R 1 R8 R9
EAS23 aa or ab -CI -Br -H
EAS24 aa or ab -Cl -Br -CI
EAS25 aa or ab -Cl -Br -Br
EAS26 aa or ab -Cl -Br -F
EAS27 aa or ab -CI -Br -CH3
EAS28 aa or ab -Cl -Br -OCH3
EAS29 aa or ab -C1 -Br -OCH2CH3
EAS30 aa or ab -Cl -Br -CF3
EAS31 aa or ab -Cl -Br -0CF3
EAS32 aa or ab -Cl -Br iso-propyl
EAS33 aa or ab -Cl -Br tert-butyl
EAS34 aa or ab -CI -F -H
EAS35 aa or ab -Cl -F -Cl
EAS36 aa or ab -C1 -F -Br
EAS37 aa or ab -C1 -F -F
EAS38 aa or ab -Cl -F -CH3
EAS39 aa or ab -Cl -F -OCH3
EAS40 aa or ab -Cl -F -OCH2CH3
EAS41 aa or ab -C1 -F -CF3
EAS42 aa or ab -C1 -F -0CF3
EAS43 aa or ab -Cl -F iso-propyl
EAS44 aa or ab -Cl -F tert-butyl
EAS45 aa or ab -Cl -CH3 -H
EAS46 aa or ab -C1 -CH3 -Cl
EAS47 aa or ab -Cl -CH3 -Br
EAS48 aa or ab -Cl -CH3 -F
EAS49 aa or ab -Cl -CH3 -CH3
EAS50 aa or ab -Cl -CH3 -OCH3
EAS51 aa or ab -CI -CH3 -OCH2CH3
EAS52 aa or ab -Cl -CH3 -CF3
EAS53 aa or ab -Cl -CH3 -0CF3
EAS54 aa or ab -Cl -CH3 iso-propyl
EAS55 aa or ab -Cl -CH3 tert-butyl
EAS56 aa or ab -Cl -OCH3 -H
EAS57 aa or ab -C1 -OCH3 -Cl
EAS58 aa or ab -Cl -OCH3 -Br
EAS59 aa or ab -Cl -OCH3 -F
EAS60 aa or ab -Cl -OCH3 -CH3
EAS61 aa or ab -Cl -OCH3 -OCH3
EAS62 aa or ab -Cl -OCH3 -OCH2CH3
EAS63 aa or ab -Cl -OCH3 -CF3
EAS64 aa or ab -Cl -OCH3 -0CF3
EAS65 aa or ab -Cl -OCH3 iso-propyl
EAS66 aa or ab -Cl -OCH3 tert-butyl
EAS67 aa or ab -Cl -OCH2CH3 -H
EAS68 aa or ab -Cl -OCH2CH3 -C1
EAS69 aa or ab -CI -OCH2CH3 -Br
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Compound R1 R8 R9
EAS70 aa or ab -C1 -OCH2CH3 -F
EAS71 aa or ab -CI -OCH2CH3 -CH3
EAS72 aa or ab -Cl -OCH2CH3 -OCH3
EAS73 aa or ab -Cl -OCH2CH3 -OCH2CH3
EAS74 aa or ab -Cl -OCH2CH3 -CF3
EAS75 aa or ab -Cl -OCH2CH3 -0CF3
EAS76 aa or ab -C1 -OCH2CH3 iso-propyl
EAS77 aa or ab -Cl -OCH2CH3 tert-butyl
EAS78 aa or ab -Cl -CF3 -H
EAS79 aa or ab -Cl -CF3 -Cl
EAS80 aa or ab -Cl -CF3 -Br
EAS81 aa or ab -Cl -CF3 -F
EAS82 aa or ab -Cl -CF3 -CH3
EAS83 aa or ab -Cl -CF3 -OCH3
EAS84 aa or ab -Cl -CF3 -OCH2CH3
EAS85 aa or ab -Cl -CF3 -CF3
EAS86 aa or ab -Cl -CF3 -0CF3
EAS87 aa or ab -Cl -CF3 iso-propyl
EAS88 aa or ab -Cl -CF3 tert-butyl
EAS89 aa or ab -Cl -0CF3 -H
EAS90 aa or ab -Cl -0CF3 -CI
EAS91 aa or ab -Cl -0CF3 -Br
EAS92 aa or ab -Cl -0CF3 -F
EAS93 aa or ab -C1 -0CF3 - -CH3
EAS94 aa or ab -Cl -0CF3 -OCH3
EAS95 aa or ab -Cl -0CF3 -OCH2CH3
EAS96 aa or ab -Cl -0CF3 -CF3
EAS97 aa or ab -Cl -0CF3 -0CF3
EAS98 aa or ab -Cl -0CF3 iso-propyl
EAS99 aa or ab -Cl -0CF3 tert-butyl
EAS100 aa or ab -Cl iso-propyl -H
EAS101 aa or ab -Cl iso-propyl -Cl
EAS102 aa or ab -Cl iso-propyl -Br
EAS103 aa or ab -CI iso-propyl -F
EAS104 aa or ab -CI iso-propyl -CH3
EAS105 aa or ab -C1 iso-propyl -OCH3
EAS106 aa or ab -Cl iso-propyl -OCH2CH3
EAS107 aa or ab -Cl iso-propyl -CF3
EAS108 aa or ab -CI iso-propyl -0CF3
EAS109 aa or ab -Cl iso-propyl iso-propyl
EAS110 aa or ab -Cl iso-propyl tert-butyl
EAS111 aa or ab -Cl tert-butyl -H
EAS112 aa or ab -Cl tert-butyl -CI
EAS113 aa or ab -Cl tert-butyl -Br
EAS114 aa or ab -C1 tert-butyl -F
EAS115 aa or ab -Cl tert-butyl -CH3
EAS116 aa or ab -Cl tert-butyl -OCH3
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Compound R1 R8 R9
EAS117 aa or ab -Cl tert-butyl -OCH2CH3
EAS1I8 aa or ab -Cl tert-butyl -CF3
EAS1I9 aa or ab -Cl tert-butyl -0CF3
EAS120 aa or ab -Cl tert-butyl iso-propyl
EAS121 aa or ab -Cl tert-butyl tert-butyl
EAT1 aa or ab -F -H -H
EAT2 aa or ab -F -H -Cl
EAT3 aa or ab -F -H -Br
EAT4 aa or ab -F -H -F
EATS aa or ab _ -F -H -CH3
EAT6 aa or ab -F -H -OCH3
EAT7 aa or ab -F -H -OCH2CH3
EAT8 aa or ab -F -H -CF3
EAT9 aa or ab -F -H -0CF3
EAT10 aa or ab -F -H iso-propyl
EATII aa or ab -F -H tert-butyl
EAT 12 aa or ab -F -Cl -H
EATI3 aa or ab -F -Cl -Cl
EAT14 aa or ab -F -Cl -Br
EATI5 aa or ab -F -Cl -F
EAT16 aa or ab -F -Cl -CH3
EAT17 aa or ab -F -Cl -OCH3
EAT 18 aa or ab -F -Cl -OCH2CH3
EATI9 aa or ab -F -Cl -CF3
EAT20 aa or ab -F -Cl -0CF3
EAT2I aa or ab -F -Cl iso-propyl
EAT22 aa or ab -F -Cl tert-butyl
EAT23 aa or ab -F -Br -H
EAT24 aa or ab -F -Br -Cl
EAT25 aa or ab -F -Br -Br
EAT26 aa or ab -F -Br -F
EAT27 aa or ab -F -Br -CH3
EAT28 aa or ab -F -Br -OCH3
EAT29 aa or ab -F -Br -OCH2CH3
EAT30 aa or ab -F -Br -CF3
EAT31 aa or ab -F -Br -0CF3
EAT32 aa or ab -F -Br iso-propyl
EAT33 aa or ab -F -Br tert-butyl
EAT34 aa or ab -F -F -H
EAT35 aa or ab -F -F -Cl
EAT36 aa or ab -F -F -Br
EAT37 aa or ab -F -F -F
EAT38 aa or ab -F -F -CH3
EAT39 aa or ab -F -F -OCH3
EAT40 aa or ab -F -F -OCH2CH3
EAT41 aa or ab -F -F -CF3
EAT42 aa or ab -F -F -0CF3
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Compound R1 R8 R9
EAT43 aa or ab -F -F iso-propyl
EAT44 aa or ab -F -F tert-butyl
EAT45 aa or ab -F -CH3 -H
EAT46 aa or ab -F -CH3 -C1
EAT47 aa or ab -F -CH3 -Br
EAT48 aa or ab -F -CH3 -F
EAT49 aa or ab -F -CH3 -CH3
EAT50 aa or ab -F -CH3 -OCH3
EAT51 aa or ab -F -CH3 -OCH2CH3
EAT52 aa or ab -F -CH3 -CF3
EAT53 aa or ab -F -CH3 -0CF3
EAT54 aa or ab -F -CH3 iso-propyl
EAT55 aa or ab -F -CH3 tert-butyl
EAT56 aa or ab -F -OCH3 -H
EAT57 aa or ab -F -OCH3 -Cl
EAT58 aa or ab -F -OCH3 -Br
EAT59 aa or ab -F -OCH3 -F
EAT60 aa or ab -F -OCH3 -CH3
EAT61 aa or ab -F -OCH3 -OCH3
EAT62 aa or ab -F -OCH3 -OCH2CH3
EAT63 aa or ab -F -OCH3 -CF3
EAT64 aa or ab -F -OCH3 -0CF3
EAT65 aa or ab -F -OCH3 iso-propyl
EAT66 aa or ab -F -OCH3 tert-butyl
EAT67 aa or ab -F -OCH2CH3 -H
EAT68 aa or ab -F -OCH2CH3 -Cl
EAT69 aa or ab -F -OCH2CH3 -Br
EAT70 aa or ab -F -OCH2CH3 -F
EAT71 aa or ab -F -OCH7CH3 -CH3
EAT72 aa or ab -F -OCH2CH3 -OCH3
EAT73 aa or ab -F -OCH2CH3 -OCH2CH3
EAT74 aa or ab -F -OCH2CH3 -CF3
EAT75 aa or ab -F -OCH2CH3 -0CF3
EAT76 aa or ab -F -OCH2CH3 iso-propyl
EAT77 aa or ab -F -OCH2CH3 tert-butyl
EAT78 aa or ab -F -CF3 -H
EAT79 aa or ab -F -CF3 -Cl
EAT80 aa or ab -F -CF3 -Br
EAT81 aa or ab -F -CF3 -F
EAT82 aa or ab -F -CF3 -CH3
EAT83 aa or ab -F -CF3 -OCH3
EAT84 aa or ab -F -CF3 -OCH2CH3
EAT85 aa or ab -F -CF3 -CF3
EAT86 aa or ab -F -CF3 -0CF3
EATS 7 aa or ab -F -CF3 iso-propyl
EAT88 aa or ab -F -CF3 tert-butyl
EAT89 aa or ab -F -0CF3 -H
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Compound R1 R8 R9
EAT90 aa or ab -F -0CF3 -Cl
EAT91 aa or ab -F -0CF3 -Br
EAT92 aa or ab -F -0CF3 -F
EAT93 aa or ab -F -0CF3 -CH3
EAT94 aa or ab -F -0CF3 -OCH3
EAT95 aa or ab -F -0CF3 -OCH2CH3
EAT96 aa or ab -F -0CF3 -CF3
EAT97 aa or ab -F -0CF3 -0CF3
EAT98 aa or ab -F -0CF3 iso-propyl
EAT99 aa or ab -F -0CF3 tert-butyl
EATIO0 aa or ab -F iso-propyl -H
EAT101 aa or ab -F iso-propyl -CI
EAT102 aa or ab -F iso-propyl -Br
EATIO3 aa or ab -F iso-propyl -F
EAT104 aa or ab -F iso-propyl -CH3
EAT105 aa or ab -F iso-propyl -OCH3
EAT106 aa or ab -F iso-propyl -OCH2CH3
EAT107 aa or ab -F iso-propyl -CF3
EAT108 aa or ab -F iso-propyl -0CF3
EAT109 aa or ab -F iso-propyl iso-propyl
EAT1I0 aa or ab -F iso-propyl tert-butyl
EATI 11 aa or ab -F tert-butyl -H
EAT! 12 aa or ab -F tert-butyl -Cl
EAT! 13 aa or ab -F tert-butyl -Br
EAT! 14 aa or ab -F tert-butyl -F
EAT115 aa or ab -F tert-butyl -CH3
EAT116 aa or ab -F tert-butyl -OCH3
EAT117 aa or ab -F tert-butyl -OCH2CH3
EAT118 aa or ab -F tert-butyl -CF3
EAT! 19 aa or ab -F tert-butyl -0CF3
EAT120 aa or ab -F tert-butyl iso-propyl
EAT121 aa or ab -F tert-butyl tert-butyl
EAUI aa or ab -CF3 -H -H
EAU2 aa or ab -CF3 -H -Cl
EAU3 aa or ab -CF3 -H -Br
EAU4 aa or ab -CF3 -H -F
EAU5 aa or ab -CF3 -H -CH3
EAU6 aa or ab -CF3 -H -OCH3
EAU7 aa or ab -CF3 -H -OCH2CH3
EAU8 aa or ab -CF3 -H -CF3
EAU9 aa or ab -CF3 -H -0CF3
EAU10 aa or ab -CF3 -H iso-propyl
EAU 1 I aa or ab -CF3 -H tert-butyl
EAU12 aa or ab -CF3 -Cl -H
EAU13 aa or ab -CF3 -Cl -Cl
EAUI4 aa or ab -CF3 -C1 -Br
EAU15 aa or ab -CF3 -Cl -F
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Compound R1 R8 R9
EAU16 aa or ab -CF3 -Cl -CH3
EAU17 aa or ab -CF3 -Cl -OCH3
EAU18 aa or ab -CF3 -Cl -OCH2CH3
EAU19 aa or ab -CF3 -Cl -CF3
EAU20 aa or ab -CF3 -Cl -0CF3
EAU21 aa or ab -CF3 -Cl iso-propyl
EAU22 aa or ab -CF3 -Cl tert-butyl
' EAU23 aa or ab -CF3 -Br -H
EAU24 aa or ab -CF3 -Br -Cl
EAU25 aa or ab -CF3 -Br -Br
EAU26 aa or ab -CF3 -Br -F
EAU27 aa or ab -CF3 -Br -CH3
EAU28 aa or ab -CF3 -Br -OCH3
EAU29 aa or ab -CF3 -Br -OCH2CH3
EAU30 aa or ab -CF3 -Br -CF3
EAU31 aa or ab -CF3 -Br -0CF3
EAU32 aa or ab -CF3 -Br iso-propyl
EAU33 aa or ab -CF3 -Br tert-butyl
EAU34 aa or ab -CF3 -F -H
EAU35 aa or ab -CF3 -F -Cl
EAU36 aa or ab -CF3 -F -Br
EAU37 aa or ab -CF3 -F -F
EAU38 aa or ab -CF3 -F -CH3
EAU39 aa or ab -CF3 -F -OCH3
EAU40 aa or ab -CF3 -F -OCH2CH3
EAU41 aa or ab -CF3 -F -CF3
EAU42 aa or ab -CF3 -F -0CF3
EAU43 aa or ab -CF3 -F iso-propyl
EAU44 aa or ab -CF3 -F tert-butyl
EAU45 aa or ab -CF3 -CH3 -H
EAU46 aa or ab -CF3 -CH3 -Cl
EAU47 aa or ab -CF3 -CH3 -Br
EAU48 aa or ab -CF3 -CH3 -F
EAU49 aa or ab -CF3 -CH3 -CH3
EAU50 aa or ab -CF3 -CH3 -OCH3
EAU51 aa or ab -CF3 -CH3 -OCH2CH3
EAU52 aa or ab -CF3 -CH3 -CF3
EAU53 aa or ab -CF3 -CH3 -0CF3
EAU54 aa or ab -CF3 -CH3 iso-propyl
EAU55 aa or ab -CF3 -CH3 tert-butyl
EAU56 aa or ab -CF3 -OCH3 -H
EAU57 aa or ab -CF3 -OCH3 -Cl
EAU58 aa or ab -CF3 -OCH3 -Br
EAU59 aa or ab -CF3 -OCH3 -F
EAU60 aa or ab -CF3 -OCH3 -CH3
EAU61 aa or ab -CF3 -OCH3 -OCH3
EAU62 aa or ab -CF3 -OCH3 -OCH2CH3
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Compound R1 R8 R9
EAU63 aa or ab -CF3 -OCH3 -CF3
EAU64 aa or ab -CF3 -OCH3 -0CF3
EAU65 aa or ab -CF3 -OCH3 iso-propyl
EAU66 aa or ab -CF3 -OCH3 tert-butyl
EAU67 aa or ab -CF3 -OCH2CH3 -H
EAU68 aa or ab -CF3 -OCH2CH3 -C1
EAU69 aa or ab -CF3 -OCH2CH3 -Br
EAU70 aa or ab -CF3 -OCH2CH3 -F
EAU71 aa or ab -CF3 -OCH2CH3 -CH3
EAU72 aa or ab -CF3 -OCH2CH3 -OCH3
EAU73 aa or ab -CF3 -OCH2CH3 -0CF7CH3
EAU74 aa or ab -CF3 -OCH7CH3 -CF3
EAU75 aa or ab -CF3 -OCH2CH3 -0CF3
EAU76 aa or ab -CF3 -OCH2CH3 iso-propyl
EAU77 aa or ab -CF3 -OCH2CH3 tert-butyl
EAU78 aa or ab -CF3 -CF3 -H
EAU79 aa or ab -CF3 -CF3 -C1
EAU80 aa or ab -CF3 -CF3 -Br
EAU81 aa or ab -CF3 -CF3 -F
EAU82 aa or ab -CF3 -CF3 -CH3
EAU83 aa or ab -CF3 -CF3 -OCH3
EAU84 aa or ab -CF3 -CF3 -OCH7CH3
EAU85 aa or ab -CF3 -CF3 -CF3
EAU86 aa or ab -CF3 -CF3 -0CF3
EAU87 aa or ab -CF3 -CF3 iso-propyl
EAU88 aa or ab -CF3 -CF3 tert-butyl
EAU89 aa or ab -CF3 -0CF3 -H
EAU90 aa or ab -CF3 -0CF3 -Cl
EAU91 aa or ab -CF3 -0CF3 -Br
EAU92 aa or ab -CF3 -0CF3 -F
EAU93 aa or ab -CF3 -0CF3 -CH3
EAU94 aa or ab -CF3 -0CF3 -OCH3
EAU95 aa or ab -CF3 -0CF3 -OCH2CH3
EAU96 aa or ab -CF3 -0CF3 -CF3
EAU97 aa or ab -CF3 -0CF3 -0CF3
EAU98 aa or ab -CF3 -0CF3 iso-propyl
EAU99 aa or ab -CF3 -0CF3 tert-butyl
EAU100 aa or ab -CF3 iso-propyl -H
EAU101 aa or ab -CF3 iso-propyl -Cl
EAU102 aa or ab -CF3 iso-propyl -Br
EAU103 aa or ab -CF3 iso-propyl -F
EAU104 aa or ab -CF3 iso-propyl -CH3
EAU105 aa or ab -CF3 iso-propyl -OCH3
EAU106 aa or ab -CF3 iso-propyl -OCH2CH3
EAU107 aa or ab -CF3 iso-propyl -CF3
EAU108 aa or ab -CF3 iso-propyl -0CF3
EAU109 aa or ab -CF3 iso-propyl iso-propyl
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Compound RI R8 R9
EAU110 aa or ab -CF3 iso-propyl tert-butyl
EAU 111 aa or ab -CF3 tert-butyl -H
EAU112 aa or ab -CF3 tert-butyl -Cl
EAU113 aa or ab -CF3 tert-butyl -Br
EAU114 aa or ab -CF3 tert-butyl -F
EAU115 aa or ab -CF3 tert-butyl -CH3
EAU116 aa or ab -CF3 tert-butyl -OCH3
EAU117 aa or ab -CF3 tert-butyl -OCH2CH3
EAU 118 aa or ab -CF3 tert-butyl -CF3
EAU119 aa or ab -CF3 tert-butyl -0CF3
EAU120 aa or ab -CF3 tert-butyl iso-propyl
EAU121 aa or ab -CF3 tert-butyl tert-butyl
EAV1 aa or ab -CH3 -H -H
EAV2 aa or ab -CH3 -H -Cl
EAV3 aa or ab -CH3 -H -Br
EAV4 aa or ab -CH3 -H -F
EAV5 aa or ab -CH3 -H -CH3
EAV6 aa or ab -CH3 -H -OCH3
EAV7 aa or ab -CH3 -H -OCH2CH3
EAV8 aa or ab -CH3 -H -CF3
EAV9 aa or ab -CH3 -H -0CF3
EAV10 aa or ab -CH3 -H iso-propyl
EAVII aa or ab -CH3 -H tert-butyl
EAV12 aa or ab -CH3 -Cl -H
EAV13 aa or ab -CH3 -Cl -Cl
EAV14 aa or ab -CH3 -CI -Br
EAVI5 aa or ab -CH3 -Cl -F
EAV16 aa or ab -CH3 -Cl -CH3
EAV17 aa or ab -CH3 -Cl -OCH3
EAV18 aa or ab -CH3 -Cl -OCH2CH3
EAV19 aa or ab -CH3 -Cl -CF3
EAV20 aa or ab -CH3 -CI -0CF3
EAV2I aa or ab -CH3 -Cl iso-propyl
EAV22 aa or ab -CH3 -Cl tert-butyl
EAV23 aa or ab -CH3 -Br -H
EAV24 aa or ab -CH3 -Br -Cl
EAV25 aa or ab -CH3 -Br -Br
EAV26 aa or ab -CH3 -Br -F
EAV27 aa or ab -CH3 -Br -CH3
EAV28 aa or ab -CH3 -Br -OCH3
EAV29 aa or ab -CH3 -Br -OCH?CH3
EAV30 aa or ab -CH3 -Br -CF3
EAV31 aa or ab -CH3 -Br -0CF3
EAV32 aa or ab -CH3 -Br iso-propyl
EAV33 aa or ab -CH3 -Br tert-butyl
EAV34 aa or ab -CH3 -F -H
EAV35 aa or ab -CH3 -F -Cl
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Compound R1 R8 R9
EAV36 aa or ab -CH3 -F -Br
EAV37 aa or ab -CH3 -F -F
EAV38 aa or ab -CH3 -F -CH3
EAV39 aa or ab -CH3 -F -OCH3
EAV40 aa or ab -CH3 -F -OCH2CH3
EAV41 aa or ab -CH3 -F -CF3
EAV42 aa or ab -CH3 -F -0CF3
EAV43 aa or ab -CH3 -F iso-propyl
EAV44 aa or ab -CH3 -F tert-butyl
EAV45 aa or ab -CH3 -CH3 -H
EAV46 aa or ab -CH3 -CH3 -Cl
EAV47 aa or ab -CH3 -CH3 -Br
EAV48 aa or ab -CH3 -CH3 -F
EAV49 aa or ab -CH3 -CH3 -CH3
EAV50 aa or ab -CH3 -CH3 -OCH3
EAV51 aa or ab -CH3 -CH3 -OCH2CH3
EAV52 aa or ab -CH3 -CH3 -CF3
EAV53 aa or ab -CH3 -CH3 -0CF3
EAV54 aa or ab -CH3 -CH3 iso-propyl
EAV55 aa or ab -CH3 -CH3 tert-butyl
EAV56 aa or ab -CH3 -OCH3 -H
EAV57 aa or ab -CH3 -OCH3 -Cl
EAV58 aa or ab -CH3 -OCH3 -Br
EAV59 aa or ab -CH3 -OCH3 -F
EAV60 aa or ab -CH3 -OCH3 -CH3
EAV61 aa or ab -CH3 -OCH3 -OCH3
EAV62 aa or ab -CH3 -OCH3 -OCH2CH3
EAV63 aa or ab -CH3 -OCH3 -CF3
EAV64 aa or ab -CH3 -OCH3 -0CF3
EAV65 aa or ab -CH3 -OCH3 iso-propyl
EAV66 aa or ab -CH3 -OCH3 tert-butyl
EAV67 aa or ab -CH3 -OCH2CH3 -H
EAV68 aa or ab -CH3 -OCH,CH3 -Cl __
EAV69 aa or ab -CH3 -OCH2CH3 -Br
EAV70 aa or ab -CH3 -OCH2CH3 -F
EAV71 aa or ab -CH3 -OCH2CH3 -CH3
EAV72 aa or ab -CH3 -OCH2CH3 -OCH3
EAV73 aa or ab -CH3 -OCE7CH3 -OCH2CH3
EAV74 aa or ab -CH3 -OCH7CH3 -CF3
EAV75 aa or ab -CH3 -OCH2CH3 -0CF3
EAV76 aa or ab -CH3 -OCH2CH3 iso-propyl
EAV77 aa or ab -CH3 -OCH2CH3 tert-butyl
EAV78 aa or ab -CH3 -CF3 -H
EAV79 aa or ab -CH3 -CF3 -Cl
EAV80 aa or ab -CH3 -CF3 -Br
EAV81 aa or ab -CH3 -CF3 -F
EAV82 aa or ab -CH3 -CF3 -CH3
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Compound R1 R8 R9
EAV83 aa or ab -CH3 -CF3 -OCH3
EAV84 aa or ab -CH3 -CF3 -OCH2CH3
EAV85 aa or ab -CH3 -CF3 -CF3
EAV86 aa or ab -CH3 -CF3 -0CF3
EAV87 aa or ab -CH3 -CF3 iso-propyl
EAV88 aa or ab -CH3 -CF3 tert-butyl
EAV89 aa or ab -CH3 -0CF3 -H
EAV90 aa or ab -CH3 -0CF3 -Cl
EAV91 aa or ab -CH3 -0CF3 -Br
EAV92 aa or ab -CH3 -0CF3 -F
EAV93 aa or ab -CH3 -0CF3 -CH3
EAV94 aa or ab -CH3 -0CF3 -OCH3
EAV95 aa or ab -CH3 -0CF3 -OCH,CH3
EAV96 aa or ab -CH3 -0CF3 -CF3
EAV97 aa or ab -CH3 -0CF3 -0CF3
EAV98 aa or ab -CH3 -0CF3 iso-propyl
EAV99 aa or ab -CH3 -0CF3 tert-butyl
EAV100 aa or ab -CH3 iso-propyl -H
EAV101 aa or ab -CH3 iso-propyl -Cl
EAV102 aa or ab -CH3 _ iso-propyl -Br
EAV103 aa or ab -CH3 iso-propyl -F
EAV104 aa or ab -CH3 iso-propyl -CH3
EAV105 aa or ab -CH3 iso-propyl -OCH3
EAV106 aa or ab -CH3 iso-propyl -OCH2CH3
EAV107 aa or ab -CH3 iso-propyl -CF3
EAV108 aa or ab -CH3 iso-propyl -0CF3
EAV109 aa or ab -CH3 iso-propyl iso-propyl
EAV110 aa or ab -CH3 iso-propyl tert-butyl
EAV111 aa or ab -CH3 tert-butyl -H
EAV112 aa or ab -CH3 tert-butyl -Cl
EAV113 aa or ab -CH3 tert-butyl -Br
EAV114 aa or ab -CH3 tert-butyl -F
EAV115 aa or ab -CH3 tert-butyl -CH3
EAV116 aa or ab -CH3 tert-butyl -OCH3
EAV117 aa or ab -CH3 tert-butyl -OCH2CH3
EAV118 aa or ab -CH3 tert-butyl -CF3
EAV119 aa or ab -CH3 tert-butyl -0CF3
EAV120 aa or ab -CH3 tert-butyl iso-propyl
EAV121 aa or ab -CH3 tert-butyl tert-butyl
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Table 28
OH
OH
1
N
R1
F
N/
0NH
N ' S
0
R9
(IlIbb)
and pharmaceutically acceptable derivatives thereof, where:
Compound R 1 R9
EBB -Cl -Cl
EBC -Cl -F
EBD -C1 -CH3
EBE -F -Cl
EBF -F -F
EBG -F -CH3
EBH -CF3 -Cl
EBI -CF3 -F
EBJ -CF3 -CH3
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Table 29
OH
OH
N
R1
0NH
NS
R9
and pharmaceutically acceptable derivatives thereof, where:
Compound R1 R9
EBK -Cl -Cl
EBL -Cl -F
EBM -Cl -CH3
EBN -F -Cl
EBO -F -F
EBP -F -CH3
EBQ -CF3 -Cl
EBR -CF3 -F
EBS -CF3 -CH3
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Table 30
OH
OH
Rry N
0NH
NS
R9
and pharmaceutically acceptable derivatives thereof, where:
Compound R1 R9
EBT -Cl -Cl
EBU -Cl -F
EBV -Cl -CH3
EBW -F -Cl
EBX -F -F
EBY -F -CH3
EBZ -CF3 -Cl
ECA -CF3 -F
ECB -CF3 -CH3
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Table 31
OH
N
ONH
3
R14'
(IIIee)
and pharmaceutically acceptable derivatives thereof, where:
Compound R1 R14.
FAA -Cl -CI
FAB -C1 -F
FAC -C1 -Br
FAD -Cl -OCH3
FAE -C1 -OCH2CH3
FAF -F -CI
FAG -F -F
FAH -F -Br
FAI -F -OCH3
FAJ -F -OCH2CH3
FAK -CF3 -CI
FAL -CF3 -F
FAM -CF3 -Br
FAN -CF3 -OCH3
FAO -CF3 -OCH2CH3
Table 32
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OHõ,
OH
O
\
N
Ri
NH
CF3
R14.
(IIIff)
and pharmaceutically acceptable derivatives thereof, where:
Compound R1 R14
FAP -Cl -Cl
FAQ -Cl -F
FAR -C1 -Br
FAS -Cl -OCH3
FAT -Cl -OCH2CH3
FAU -F -Cl
FAV -F -F
FAW -F -Br
FAX -F -OCH3
FAY -F -OCH2CH3
FAZ -CF3 -Cl
FBA -CF3 -F
FBB -CF3 -Br
FBC -CF3 -OCH3
FBD -CF3 -OCH2CH3
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Table 33
OH,
'COH
\
RN
0NH
CF3
R14
(IIIgg)
and pharmaceutically acceptable derivatives thereof, where:
Compound R1 R14.
FBE -Cl -Cl
FBF -Cl -F
FBG -Cl -Br
FBH -Cl -OCH3
FBI -Cl -OCH2CH3
FBJ -F -C1
FBK -F -F
FBL -F -Br
FBM -F -OCH3
FBN -F -OCH2CH3
FBO -CF3 -Cl
FBP -CF3 -F
FBQ -CF3 -Br
FBR -CF3 -OCH3
FBS -CF3 -OCH2CH3
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Table 34
OH
OH
\
N
R1
O NH
õ
3
R14'
(IIIhh)
and pharmaceutically acceptable derivatives thereof, where:
Compound RI R14
FBT -Cl -Cl
FBU -Cl -F
FBV -Cl -Br
FBW -Cl -OCH3
FBX -Cl -OCH2CH3
FBY -F -Cl
FBZ -F -F
FCA -F -Br
FCB -F -OCH3
FCC -F -OCH2CH3
FCD -CF3 -Cl
FCE -CF3 -F
FCF -CF3 -Br
FCG -CF3 -OCH3
FCH -CF3 -OCH2CH3
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Table 35
OH
OH
N
0NH
CF3
R14(11111)
and pharmaceutically acceptable derivatives thereof, where:
Compound RI R 14
FCI -Cl -Cl
FCJ -Cl -F
FCK -Cl -Br
FCL -Cl -OCH3
FCM -Cl -OCH2CH3
FCN -F -Cl
FCO -F -F
FCP -F -Br
FCQ -F -OCH3
FCR -F -OCH2CH3
FCS -CF3 -Cl
FCT -CF3 -F
FCU -CF3 -Br
FCV -CF3 -OCH3
FCW -CF3 -OCH2CH3
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Table 36
OH
COH
0NH
1101 CF3
R14'
(Injj)
and pharmaceutically acceptable derivatives thereof, where:
Compound R1 R14.
FCX -Cl -Cl
FCY -Cl -F
FCZ -Cl -Br
FDA -Cl -OCH3
FDB -Cl -OCH2CH3
FDC -F -Cl
FDD -F -F
FDE -F -Br
FDF -F -OCH3
FDG -F -OCH2CH3
FDH -CF3 -Cl
FDI -CF3 -F
FDJ -CF3 -Br
FDK -CF3 -OCH3
FDL -CF3 -OCH2CH3
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5.4 DEFINITIONS
As used herein, the terms used above having following meaning:
"-(CI-Cio)alkyl" means a straight chain or branched non-cyclic hydrocarbon
having from 1 to 10 carbon atoms. Representative straight chain -(Ci-
Cio)alkyls include
-methyl, -ethyl, -n-propyl, -n-butyl, -n-pentyl, -n-hexyl, -n-heptyl, -n-
octyl, -n-nonyl,
and -n-decyl. Representative branched -(C1-C10)alkyls include -iso-propyl, -
sec-butyl,
-iso-butyl, -tert-butyl, -iso-pentyl, -neo-pentyl, 1-methylbutyl, 2-
methylbutyl,
3-methylbutyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 1-methylpentyl,
2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1-ethylbutyl, 2-ethylbutyl,
3-ethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl,
2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-methylhexyl, 2-
methylhexyl,
3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 1,2-dimethylpentyl, 1,3-
dimethylpentyl,
1,2-dimethylhexyl, 1,3-dimethylhexyl, 3,3-dimethylhexyl, 1,2-dimethylheptyl,
1,3-dimethylheptyl, and 3,3-dimethylheptyl.
"-(CI-C6)alkyl" means a straight chain or branched non-cyclic hydrocarbon
having from 1 to 6 carbon atoms. Representative straight chain -(Ci-C6)alkyls
include
-methyl, -ethyl, -n-propyl, -n-butyl, -n-pentyl, and -n-hexyl. Representative
branched
-(CI-C6)alkyls include -iso-propyl, -sec-butyl, -iso-butyl, -tert-butyl, -iso-
pentyl,
-neo-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 1,1-dimethylpropyl,
1,2-dimethylpropyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-
methylpentyl,
1-ethylbutyl, 2-ethylbutyl, 3-ethylbutyl, 1,1-dimethtylbutyl, 1,2-
dimethylbutyl,
1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, and 3,3-
dimethylbutyl.
"-(C1-C6)haloalkyl" means a straight chain or branched non-cyclic hydrocarbon
having from 1 to 6 carbon atoms as defined above for ¨(CI-C6)alkyl that is
substituted
with 1, 2 or 3 independently selected halo groups.
"-(C1-C6)hydroxyalkyl" means a straight chain or branched non-cyclic
hydrocarbon having from 1 to 6 carbon atoms as defined above for ¨(Ci-C6)alkyl
that is
substituted with 1, 2 or 3 hydroxyl groups.
"-(CI-C4)alky1" means a straight chain or branched non-cyclic hydrocarbon
having from 1 to 4 carbon atoms. Representative straight chain -(CI-C4)alkyls
include
-methyl, -ethyl, -n-propyl, and -n-butyl. Representative branched -(CI-
C4)alkyls include
-iso-propyl, -sec-butyl, -iso-butyl, and -tert-butyl.
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"-(C2-C10)alkenyl" means a straight chain or branched non-cyclic hydrocarbon
having from 2 to 10 carbon atoms and including at least one carbon-carbon
double bond.
Representative straight chain and branched (C2-C10)alkenyls include -vinyl, -
allyl,
-1-butenyl, -2-butenyl, -iso-butylenyl, -1-pentenyl, -2-pentenyl, -3-methyl- 1
-butenyl,
-2-methy1-2-butenyl, -2,3-dimethy1-2-butenyl, -1-hexenyl, -2-hexenyl, -3-
hexenyl,
-1-heptenyl, -2-heptenyl, -3-heptenyl, -1-octenyl, -2-octenyl, -3-octenyl, -1-
nonenyl,
-2-nonenyl, -3-nonenyl, -1-decenyl, -2-decenyl, -3-decenyl and the like.
"-(C2-C6)alkenyl" means a straight chain or branched non-cyclic hydrocarbon
having from 2 to 6 carbon atoms and including at least one carbon-carbon
double bond.
Representative straight chain and branched (C2-C6)alkenyls include -vinyl, -
allyl,
-1-butenyl, -2-butenyl, -iso-butylenyl, -1-pentenyl, -2-pentenyl, -3-methyl- 1
-butenyl,
-2-methyl-2-butenyl, -2,3-dimethy1-2-butenyl, -1-hexenyl, 2-hexenyl, 3-hexenyl
and the
like.
"-(C7-C6)haloalkenyl" means a straight chain or branched non-cyclic
hydrocarbon having from 2 to 6 carbon atoms and including at least one carbon-
carbon
double bond as defined above for -(C2-C6)alkenyl that is substituted with 1, 2
or 3
independently selected halo groups.
"-(C7-C6)hydroxyalkenyl" means a straight chain or branched non-cyclic
hydrocarbon having from 2 to 6 carbon atoms and including at least one carbon-
carbon
double bond as defined above for -(C2-C6)alkenyl that is substituted with 1, 2
or 3
hydroxyl groups.
"-(C2-Cio)alkynyl" means a straight chain or branched non-cyclic hydrocarbon
having from 2 to 10 carbon atoms and including at least one carbon-carbon
triple bond.
Representative straight chain and branched -(C,-Cio)alkynyls include -
acetylenyl,
-propynyl, -1-butynyl, -2-butynyl, -1-pentynyl, -2-pentynyl, -3-methyl-1 -
butynyl,
-4-pentynyl, -1-hexynyl, -2-hexynyl, -5-hexynyl, -1-heptynyl, -2-heptynyl, -6-
heptynyl,
-1-octynyl, -2-octynyl, -7-octynyl, -1-nonynyl, -2-nonynyl, -8-nonynyl, -1-
decynyl,
-2-decynyl, -9-decynyl and the like.
"-(C2-C6)alkynyl" means a straight chain or branched non-cyclic hydrocarbon
having from 2 to 6 carbon atoms and including at least one carbon-carbon
triple bond.
Representative straight chain and branched (C2-C6)alkynyls include -
acetylenyl,
-propynyl, -1-butynyl, -2-butynyl, -1-pentynyl, -2-pentynyl, -3-methyl-1-
butynyl,
-4-pentynyl, -1-hexynyl, -2-hexynyl, -5-hexynyl and the like.
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"-(C2-C6)haloalkynyl" means a straight chain or branched non-cyclic
hydrocarbon having from 2 to 6 carbon atoms and including at least one carbon-
carbon
triple bond that is substituted with 1, 2 or 3 independently selected halo
groups.
" -(C2-C6)hydroxyalkynyl" means a straight chain or branched non-cyclic
hydrocarbon having from 2 to 6 carbon atoms and including at least one carbon-
carbon
triple bond that is substituted with 1, 2 or 3 hydroxyl groups.
"-(C1-C6)alkoxy" means a straight chain or branched non cyclic hydrocarbon
having one or more ether groups and from 1 to 6 carbon atoms. Representative
straight
chain and branched -(Ci-C6)alkoxys include methoxy, ethoxy, propoxy, butoxy,
pentoxy, hexoxy, methoxymethyl, 2-methoxyethyl, 5-methoxypentyl, 3-
ethoxybutyl,
and the like.
"-(C1-C6)alkoxy(C2-C6)alkyl" means a straight chain or branched non cyclic
hydrocarbon having one or more ether groups and from 1 to 6 carbon atoms as
defined
above for ¨(Ci-C6)alkoxy group that is substituted with a -(C2-C6)alkyl group.
"-(Ci-C6)alkoxy(C2-C6)alkenyl" means a straight chain or branched non cyclic
hydrocarbon having one or more ether groups and from 1 to 6 carbon atoms as
defined
above for ¨(CI-C6)alkoxy group that is substituted with a -(C7-C6)alkenyl
group.
"-(C1-C6)alkoxy(C2-C6)alkynyl" means a straight chain or branched non cyclic
hydrocarbon having one or more ether groups and from 1 to 6 carbon atoms that
is
substituted with a -(C2-C6)alkynyl group.
"-(CI-C6)alkoxy(C3-C8)cycloalkyl" means a straight chain or branched non
cyclic hydrocarbon having one or more ether groups and from 1 to 6 carbon
atoms as
defined above for ¨(Ci-C6)alkyl group that is substituted with a -(C3-
C8)cycloalkyl
group
"-(C3-Cio)cycloalkyl" means a saturated cyclic hydrocarbon having from 3 to 10
carbon atoms. Representative (C3-Cio)cycloalkyls are -cyclopropyl, -
cyclobutyl,
-cyclopentyl, -cyclohexyl, -cycloheptyl, -cyclooctyl, -cyclononyl, and -
cyclodecyl.
"-(C3-C8)cycloalkyl" means a saturated cyclic hydrocarbon having from 3 to 8
carbon atoms. Representative (C3-C8)cycloalkyls include -cyclopropyl, -
cyclobutyl,
-cyclopentyl, -cyclohexyl, -cycloheptyl, and -cyclooctyl.
"-(C5-C8)cycloalkenyl" means a cyclic non-aromatic hydrocarbon having at least
one carbon-carbon double bond in the cyclic system and from 5 to 8 carbon
atoms.
Representative -(C5-C8)cycloalkenyls include -cyclopentenyl, -
cyclopentadienyl,
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-cyclohexenyl, -cyclohexadienyl, -cycloheptenyl, -cycloheptadienyl, -
cycloheptatrienyl,
-cyclooctenyl, -cyclooctadienyl, -cyclooctatrienyl, -cyclooctatetraenyl and
the like.
"-(3- to 7-membered)heterocycle" or "-(3- to 7-membered)heterocyclo" means a
3- to 7-membered monocyclic heterocyclic ring which is either saturated,
unsaturated
non-aromatic, or aromatic. A 3-membered heterocycle can contain up to 1
heteroatom, a
4-membered heterocycle can contain up to 2 heteroatoms, a 5-membered
heterocycle
can contain up to 4 heteroatoms, a 6-membered heterocycle can contain up to 4
heteroatoms, and a 7-membered heterocycle can contain up to 5 heteroatoms.
Each
heteroatom is independently selected from nitrogen, which can be quatemized;
oxygen;
and sulfur, including sulfoxide and sulfone. The -(3- to 7-
membered)heterocycle can be
attached via a nitrogen or carbon atom. Representative -(3- to 7-
membered)heterocycles
include pyridyl, furyl, thiophenyl, pyrrolyl, oxazolyl, imidazolyl,
thiazolidinyl,
thiadiazolyl, thiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, pyridazinyl,
pyrimidinyl,
triazinyl, morpholinyl, pyrrolidinonyl, pyrrolidinyl, piperidinyl,
piperazinyl, 2,3-
dihydrofuranyl, dihydropyranyl, hydantoinyl, valerolactamyl, oxiranyl,
oxetanyl,
tetrahydrofuranyl, tetrahydropyranyl, dihydropyridinyl, tetrahydropyridinyl,
tetrahydropyrimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, and the
like.
"-(5- to 10-membered)heteroaryl" means an aromatic heterocycle ring of 5 to 10
members, including both mono- and bicyclic ring systems, where at least one
carbon
atom of one or both of the rings is replaced with a heteroatom independently
selected
from nitrogen, oxygen, and sulfur, or at least two carbon atoms of one or both
of the
rings are replaced with a heteroatom independently selected from nitrogen,
oxygen, and
sulfur. In one embodiment, one of the -(5- to 10-membered)heteroaryl's rings
contain at
least one carbon atom. In another embodiment, both of the -(5- to 10-
membered)heteroaryl's rings contain at least one carbon atom. Representative -
(5- to
10-membered)heteroaryls include pyridyl, furyl, benzofuranyl, thiophenyl,
benzothiophenyl, quinolinyl, isoquinolinyl, pyrrolyl, indolyl, oxazolyl,
benzoxazolyl,
imidazolyl, benzimidazolyl, thiazolyl, benzothiazolyl, isoxazolyl,
oxadiazolinyl,
pyrazolyl, isothiazolyl, pyridazinyl, pyrimidyl, pyrimidinyl, pyrazinyl,
thiadiazolyl,
triazinyl, thienyl, cinnolinyl, phthalazinyl, and quinazolinyl.
"-(5- or 6-membered)heteroaryl" means a monocyclic aromatic heterocycle ring
of 5 or 6 members where at least one carbon atom is replaced with a heteroatom
independently selected from nitrogen, oxygen, and sulfur. In one embodiment,
one of
the -(5- or 6-membered)heteroaryl's ring contains at least one carbon atom.
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Representative -(5- or 6-membered)heteroaryls include pyridyl, furyl,
pyrrolyl, oxazolyl,
imidazolyl, thiazolyl, isoxazolyl, 1,2,3-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-
oxadiazolyl, 1,2,3-triazolyl, pyrazolyl, isothiazolyl, pyridazinyl, pyrimidyl,
pyrazinyl,
1,2,3-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,5-triazinyl,
and thiophenyl.
"-CH2(halo)" means a methyl group where one of the hydrogens of the methyl
group has been replaced with a halogen. Representative -CH2(halo) groups
include
-CH2F, -CH2C1, -CH2Br, and -CH21.
"-CH(halo)2" means a methyl group where two of the hydrogens of the methyl
group have been replaced with a halogen. Representative -CH(halo)2 groups
include
-CHF2, -CHC12, -CHBr2, CHBrCI, CHC1I, and -CHI,.
"-C(halo)3" means a methyl group where each of the hydrogens of the methyl
group has been replaced with a halogen. Representative -C(halo)3 groups
include -CF3,
-CC13, -CBr3, and -C13.
"-Halogen" or "-Halo" means -F, -Cl, -Br, or -I.
"(C2-C6)bridge" as used herein means a hydrocarbon chain containing 2 to 6
carbon atoms joining two atoms of the piperidine, 1,2,3,6-tetrahydropyridine
or
piperazine ring of the compounds of formulas I, II and/or III to form a fused
bicyclic
ring system. The positions of the piperidine, 1,2,3,6-tetrahydropyridine or
piperazine
ring are denoted as follows:
Ari.\A( R4 Ar1. ,R4 Ari. -R4
2/N5
3( 33CWT(R
N)6 3 m 2 \N/6
R20 R20 ,H
Xl\r
X N =
Ar2 Ar2 Ar2
(I) (II) (III)
For example, compounds of the invention can comprise a (C2-C6)bridge joining
positions 2 and 6 of the piperidine, 1,2,3,6-tetrahydropyridine or piperazine
ring (two R3
groups can together form a (C2-C6)bridge). Examples of compounds where two R3
groups can together form a (C2-C6)bridge include compounds comprising the
following
ring systems: 8-aza-bicyclo[3.2.1]octane; 8-azabicyclo[3.2.1]oct-3-ene; 3,8-
diazabicyclo[3.2.1]octane; 8-azabicyclo[3.2.1]oct-6-ene; 8-
azabicyclo[3.2.1]octa-3,6-
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diene; 3,8-diazabicyclo[3.2.1]oct-6-ene; 9-aza-bicyclo[3.3.1]nonane; 9-
azabicyclo[3.3.1]non-3-ene; 9-azabicyclo[3.3.1]non-6-ene; 9-
azabicyclo[3.3.1]nona-3,6-
diene; 9-azabicyclo[3.3.1]nona-3,7-diene; 3,9-diazabicyclo[3.3.1]nonane; 3,9-
diazabicyclo[3.3.1]non-6-ene; 3,9-diazabicyclo[3.3.1]non-7-ene; 10-aza-
bicyclo[4.3.1]decane; 10-azabicyclo[4.3.1]dec-8-ene; 8,10-
diazabicyclo[4.3.1]decane;
8,10-diazabicyclo[4.3.1]dec-3-ene; 8,10-diazabicyclo[4.3.1]dec-4-ene; 8-
azabicyclo[4.3.1]dec-4-ene; 8-azabicyclo[4.3.1]dec-3-ene; 8-
azabicyclo[4.3.1]deca-
2,6(10)-diene; 8-azabicyclo[4.3.1]deca-3,6(10)-diene; 8-azabicyclo[4.3.1]deca-
4,6(10)-
diene; 11-aza-bicyclo[5.3.1]undecane; 11-azabicyclo[5.3.1]undec-8-ene; 9,11-
diazabicyclo[5.3.1]undecane; 12-aza-bicyclo[6.3.1]dodecane; 12-
azabicyclo[6.3.1]dodec-9-ene; and 10,12-diazabicyclo[6.3.1]dodecane.
In connection with the Ar2 group
I ¨(Ria)t
ii
Y2 '
\(Y3)c E
when E is -NH(CI-C6)alkyl it is to be understood that the dashed line in the
above Ar2
group is absent, i.e., the Ar2 group is
71 j. 4)i
Nr
Y2
No(3)c NH(C1-C6)alkyl
where Y1, Y2, Y3, R14, c and tare as defined above for compounds of formula I.
When
E is =0, =S, =C(C1-05)alkyl, =C(Ci-05)alkenyl, or =N-0R20, it is to be
understood that
the dashed line in the above Ar2 group is present, i.e., the Ar2 group is
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yr-(R14)t
Yi Yi
1 1
, , I
Y2 Y2
\(Y3)C S Y2\(y3)c CH(Ci-05)alkyl
yr--(R14)t I ¨(R14)t
, or /
Yi
1 i ,
Y2=(y3k CH(C1-05)alkenyl Y2=, N-OR20
(Y3 k
respectively, where Y1, Y2, Y3, RI4, R20, C and t are as defined above for
compounds of
formula I.
The phrase "pyridyl group" means
(R2)n (R2)n (RA] .N (R2)n
..\ N
r.....
()N 1 1 1
R1 ,..---1,....N , R1 ' or
Ri
--õ,, ..,¨,.." vv., ..,..õ¨ ,
where RI, R7, and n are as defined above for compounds of formula I, and where
the
numbers designate the position of each atom in the ring.
The phrase "pyrazinyl group" means
(R2)p
Ri N
where RI, R2, and p are as defined above for compounds of formula I.
The phrase "pyrimidinyl group" means
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(R2)p oN
N N
RIN or
Ri
l/NJWYVY,
\MAMMA
where RI, R2, and pare as defined above for compounds of formula I.
The phrase "pyridazinyl group" means
NN (R2)p .N, (R2)p
N N
T(R2)p
or
Ri
SAMANNA VVVVVVVV\ VVVVVVV,
where RI, R2, and pare as defined above for compounds of formula I.
The phrase "benzoimidiazolyl group" means
N R
NN¨ " N¨ 20
R8 R9
where Rg, R9, and R20 are as defined above for compounds of formula I.
The phrase "benzothiazolyl group" means
JVVVV,
N-\s
R8
R9 ,
where Rg and R9 are as defined above for compounds of formula I.
The phrase "benzooxazolyl group" means
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,./VVW
N 0
R8
R9
where R8 and R9 are as defined above for compounds of formula I.
The phrase phenyl group means
vvvv,vv,
where R14 and s are as defined for compounds of formula I.
The phrase "tetrahydropyridyl" means
2 ;VR36
- =
where the numbers designate the position of each atom of the tetrahydropyridyl
ring.
The term "animal," includes, but is not limited to, a cow, monkey, baboon,
chimpanzee, horse, sheep, pig, chicken, turkey, quail, cat, dog, mouse, rat,
rabbit, guinea
pig, and human.
The phrase "pharmaceutically acceptable derivative," as used herein, includes
any pharmaceutically acceptable salt, solvate, radiolabeled, stereoisomer,
enantiomer,
diastereomer, other stereoisomeric form, racemic mixture, geometric isomer,
and/or
tautomer, e.g,, of a compound of formula I of the invention. In one
embodiment, the
pharmaceutically acceptable derivative is a pharmaceutically acceptable salt,
solvate,
radiolabeled, stereoisomer, enantiomer, diastereomer, other stereoisomeric
form,
racemic mixture, geometric isomer, and/or tautomer, e.g., of a compound of
formula I of
RECTIFIED SHEET (RULE 91) ISA/EP
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the invention. In another embodiment, the pharmaceutically acceptable
derivative is a
pharmaceutically acceptable salt, e.g., of a compound of formula I of the
invention.
The phrase "pharmaceutically acceptable salt," as used herein, is any
pharmaceutically acceptable salt that can be prepared from a compound of
formula I
including a salt formed from an acid and a basic functional group, such as a
nitrogen
group, of a compound of formula I. Illustrative salts include, but are not
limited, to
sulfate, citrate, acetate, trifluoroacetate, oxalate, chloride, bromide,
iodide, nitrate,
bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid
citrate,
tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate,
maleate,
gent isinate, fumarate, gluconate, glucoronate, saccharate, formate, benzoate,
glutamate,
rriethanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and
pamoate
(i.e., 1,1'-methylene-bis-(2-hydroxy-3-naphthoate)) salts. The term
"pharmaceutically
acceptable salt" also includes a salt prepared from a compound of formula I
having an
acidic functional group, such as a carboxylic acid functional group, and a
pharmaceutically acceptable inorganic or organic base. Suitable bases include,
but are
not limited to, hydroxides of alkali metals such as sodium, potassium, cesium,
and
lithium; hydroxides of alkaline earth metal such as calcium and magnesium;
hydroxides
of other metals, such as aluminum and zinc; ammonia and organic amines, such
as
unsubstituted or hydroxy-substituted mono-, di-, or trialkylamines;
dicyclohexylamine;
tributyl amine; pyridine; picoline; N-methyl,N-ethylamine; diethylamine;
triethylamine;
mono-, bis-, or tris-(2-hydroxy-(C1-C3)alkyl amines), such as mono-, his-, or
tris-(2-hydroxyethyl)amine, 2-hydroxy-tert-butylamine, or
tris-(hydroxymethypmethylamine, N,N-di-[(C,-C3)alkyl] -N-(hydroxy-(Ci-
C3)alkyl)-amines, such as N,N-dimethyl-N-(2-hydroxyethyl)amine, or
tri-(2-hydroxyethyl)amine; N-methyl-D-glucamine; and amino acids such as
arginine,
lysine, and the like. One skilled in the art will recognize that, e.g., acid
addition salts of
a compound of formula I can be prepared by reaction of the compounds with the
appropriate acid via a variety of known methods.
Compounds of formula I encompass all solvates of compounds of formula I.
"Solvates" are known in the art and are considered to be a combination,
physical
association and/or solvation of a compound of formula I with a solvent
molecule, e.g., a
disolvate, monosolvate or hemisolvate when the ratio of the solvent molecule
to the
molecule of the compound of formula I is 2:1, 1:1 or 1:2, respectively. This
physical
association involves varying degrees of ionic and covalent bonding, including
hydrogen
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bonding. In certain instances, the solvate can be isolated, for example when
one or more
solvent molecules are incorporated into the crystal lattice of a crystalline
solid. Thus,
"solvate," as used herein, encompasses both solution-phase and isolatable
solvates. A
compound of formula I of the invention may be present as a solvated form with
a
pharmaceutically acceptable solvent, such as water, methanol, ethanol, and the
like, and
it is intended that the invention include both solvated and unsolvated
compound of
formula I forms. As "hydrate" relates to a particular subgroup of solvates,
i.e., where
the solvent molecule is water, hydrates are included within the solvates of
the invention.
Preparation of solvates is known in the art. For example, M. Caira et al., J.
Pharmaceut.
Sci., 93(3):601-611 (2004), describes the preparation of solvates of
fluconazole with
ethyl acetate and with water. Similar preparations of solvates, hemisolvate,
hydrates,
and the like are described by E.C. van Tonder et al., AAPS Pharm. Sci. Tech.,
5(1),
article 12 (2004), and A.L. Bingham et al., Chem. Commun., 603-604 (2001). A
typical,
non-limiting, process involves dissolving the compound of formula I in a
desired
amount of the desired solvent (organic, water or mixtures thereof) at
temperatures above
about 20 C to about 25 C, cooling the solution at a rate sufficient to form
crystals, and
isolating the crystals by known methods, e.g., filtration. Analytical
techniques, for
example, infrared spectroscopy, can be used to show the presence of the
solvent in a
crystal of the solvate.
The invention disclosed herein is also meant to encompass all prodrugs of the
compounds of the invention. "Prodrugs" are known in the art and, while not
necessarily
possessing any pharmaceutical activity as such, are considered to be any
covalently
bonded carrier(s) that releases the active parent drug in vivo. In general,
such prodrugs
will be a functional derivative of a compound of formula I, II and/or III
which is readily
convertible in vivo, e.g., by being metabolized, into the required compound of
formula I,
II and/or III. Conventional procedures for the selection and preparation of
suitable
prodrug derivatives are described in, for example, Design of Prodrugs, H.
Bundgaard
ed., Elsevier (1985); "Drug and Enzyme Targeting, Part A," K. Widder etal.
eds., Vol.
112 in Methods in Enzymology, Academic Press (1985); Bundgaard, "Design and
Application of Prodrugs," Chapter 5 (pp. 113-191) in A Textbook of Drug Design
and
Development, P. Krogsgaard-Larsen and H. Bundgaard eds., Harwood Academic
Publishers (1991); Bundgaard et al., Adv. Drug Delivery Revs. 8:1-38 (1992);
Bundgaard etal., J. Pharmaceut. Sci. 77:285 (1988); and Kakeya etal., Chem.
Pharm.
Bull. 32:692 (1984).
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In addition, one or more hydrogen, carbon or other atoms of a compound of
formula I can be replaced by an isotope of the hydrogen, carbon or other
atoms.
Compounds of formula I include all radiolabeled forms of compounds of formula
I.
Such a "radiolabeled," "radiolabeled form", and the like of a compound of
formula I,
each of which is encompassed by the invention, is useful as a research and/or
diagnostic
tool in metabolism pharmacokinetic studies and in binding assays. Examples of
isotopes
that can be incorporated into a compound of formula I of the invention include
isotopes
of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine and
chlorine, such
as 2H, 3H, 13C, 14C, 15N, 180, 170,31P, "P, 35S, 18F, and "Cl, respectively.
Radiolabeled
compounds of the invention can be prepared by methods known in the art. For
example,
tritiated compounds of formula I can be prepared by introducing tritium into
the
particular compound of Formula I, for example, by catalytic dehalogenation
with
tritium. This method may include reacting a suitably halogen-substituted
precursor of a
compound of Formula I with tritium gas in the presence of a suitable catalyst,
for
example, Pd/C, in the presence or absence of a base. Other suitable methods
for
preparing tritiated compounds can be found in Filer, Isotopes in the Physical
and
Biomedical Sciences, Vol. I, Labeled Compounds (Part A), Chapter 6 (1987).
14C-labeled compounds can be prepared by employing starting materials having a
14C
carbon.
A compound of formula I can contain one or more asymmetric centers and may
thus give rise to enantiomers, diastereomers, and other stereoisomeric forms.
Compounds of formula I encompass all such possible forms as well as their
racemic and
resolved forms or any mixture thereof. When a compound of formula I contains
an
olefinic double bond or other center of geometric asymmetry, and unless
specified
otherwise, it is intended to include all "geometric isomers," e.g., both E and
Z geometric
isomers. All "tautomers," e.g., ketone-enol, amide-imidic acid, lactam-lactim,
enamine-
imine, amine-imine, and enamine-enimine tautomers, are intended to be
encompassed by
the invention as well.
As used herein, the terms "stereoisomer," "stereoisomeric form", and the like
are
general terms for all isomers of individual molecules that differ only in the
orientation of
their atoms in space. It includes enantiomers and isomers of compounds with
more than
one chiral center that are not mirror images of one another ("diastereomers").
The term "chiral center" refers to a carbon atom to which four different
groups
are attached.
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The term "enantiomer" or "enantiomeric" refers to a molecule that is
nonsuperimposeable on its mirror image and hence optically active where the
enantiomer rotates the plane of polarized light in one direction and its
mirror image
rotates the plane of polarized light in the opposite direction.
The term "racemic" refers to a mixture of equal parts of enantiomers which is
optically inactive.
The term "resolution" refers to the separation or concentration or depletion
of
one of the two enantiomeric forms of a molecule.
Optical isomers of a compound of formula I can be obtained by known
techniques such as chiral chromatography or formation of diastereomeric salts
from an
optically active acid or base.
Optical purity can be stated in terms of enantiomeric excess (% ee), which is
determined by the formula:
major enantiomer(mol) - minor enantiomer(mol)
x100%
major enantiomer(mol) + minor enantiomer(mol)
The phrase "effective amount," when used in connection with a compound of
formula I means an amount effective for: (a) treating or preventing a
Condition; or (b)
inhibiting TRPV1 function in a cell.
The phrase "effective amount," when used in connection with the another
therapeutic agent means an amount for providing the therapeutic effect of the
therapeutic
agent.
The phrase "therapeutic index," describes the gap between the dose that is
effective, and the dose that induces adverse effects.
When a first group is "substituted with one or more" second groups, one or
more
hydrogen atoms of the first group is replaced with a corresponding number of
second
groups. When the number of second groups is two or greater, each second group
can be
the same or different. In one embodiment, the number of second groups is one
or two.
In another embodiment, the number of second groups is one.
The term "Me0H" means methanol, i.e., methyl alcohol.
The term "Et0H" means ethanol, i.e., ethyl alcohol.
The term "t-BuOH" means tert-butyl alcohol, i.e., 2-methylpropan-2-ol.
The term "THF" means tetrahydrofuran.
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The term "DMF" means N,N-dimethylformamide.
The term "DCM" means methylene chloride, i.e., dichloromethane.
The term "DCE" means dichloroethane.
The term "DME" means 1,2-dimethoxyethane, i.e., ethylene glycol dimethyl
ether.
The term "Et0Ac" means ethyl acetate.
The term "NH4OH" means ammonium hydroxide.
The term "TEA" means triethylamine.
The term "MeCN" means acetonitrile.
The term "NaH" means sodium hydride.
The term "AcOH" means acetic acid.
The term "DIEA" means N,N-diisopropylethylamine or N-
ethyldiisopropylamine, i.e., N-ethyl-N-isopropylpropan-2-amine.
The term "DMSO" means dimethylsulfoxide, i.e., methylsulfinylmethane.
The term "DAST" means (diethylamino) sulfur trifluoride.
The term "LiHMDS" means lithium hexamethyldisilazide.
The term "BuLi" means butyl lithium.
The term "DPPP" means 1,3-bis(diphenylphosphino)propane.
The term "BOC" means tert-butyloxycarbonyl:
o r
CH3
1Zzzzzzo
CH3
The term "TBS" means tert-butyldimethylsilyl:
CH3 CH3
( CH3
CH3
CH3
The term "Ts0H" means p-toluenesulfonic acid or toluene-4-sulfonic acid.
The term "TMSBr" means trimethylsilyl bromide or (CH3)3SiBr.
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The term "TMSCI" means trimethylsilyl chloride or (CH3)3SiCI.
The term "IBD" means inflammatory-bowel disease.
The term "IBS" means irritable-bowel syndrome.
The term "ALS" means amyotrophic lateral sclerosis.
The phrases "treatment of," "treating" and the like include the amelioration
or
cessation of a Condition or a symptom thereof.
In one embodiment, treating includes inhibiting, for example, decreasing the
overall frequency of episodes of a Condition or a symptom thereof.
The phrases "prevention of," "preventing" and the like include the avoidance
of
the onset of a Condition or a symptom thereof.
5.5 METHODS FOR MAKING COMPOUNDS OF FORMULA I
The compounds of formula I can be made using conventional organic synthesis
or by the illustrative methods shown in the schemes below.
5.5.1 Methods for Making Compounds of Formula I where W is C and the
Dashed Line is Absent
The compounds of formula I where W is C and the dashed line is absent, i.e.,
"Piperidine Compounds," can be made using conventional organic synthesis or by
the
illustrative methods shown in the schemes below.
5.5.1.1 Methods for Making the Piperidine Compounds where X is 0 and 114
is ¨OH or ¨F
The compounds of formula I where X is 0 and R4 is -OH can be obtained by the
illustrative Method shown below in scheme 1.1:
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Scheme 1.1
( R2 )n----C N
\ I OH
0 Ri
T-(R3),õ I I t-butyl lithium/-78 C N
N
+ Ri N THF ONH
1
ONH L Ar2
1 Piperidine Compound 3a
Ar2 2a
1
N:::11-1
R1
(R2)p\õ( N
-N1 t-butyl Iithium/-78 C
THF ONH
Ri
1 + I
L Ar2
2b Piperidine Compound 3b
(R2)p.s.ti -\ N
\ / OH
(R2)p\1\1 R1
1 )1\1 y(R36
N
1
R t-butyl lithium/-78% __., + 1
THF
L NH
I
2c Ar2
Piperidine Compound 3c
(R2)p-----C-;zNµN .
\ 1 OH
(R2)p\ N R1
I M y(R36
N
R1'' t-butyl lithium/-78 C0
1 + THF ONH
L 1
2d Ar2
Piperidine Compound 3d
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where Ar), RI, R2, R3, n, m, and pare as defined for compounds of formula 1
and L is a
halogen.
To a solution of 2a-d in the presence of tert-butyl lithium (1.7M in heptane,
6.45mL, 11.12mmol) in THF (20mL) at -78 C is added dropwise compound 1 in
anhydrous THF (10mL). The reaction mixture is stirred at -78 C for about 3h
and is
quenched with aqueous NH4C1 at about 0 C, and then the organic and aqueous
layers are
separated. The aqueous layer is extracted with THF, the organic portions are
combined,
and dried (Na2SO4). The resulting solution is concentrated under reduced
pressure to
provide a residue. The residue is chromatographed using silica gel column
chromatography that is eluted with ethyl acetate/hexane (gradient elution from
30:70 to
70:30) to provide a Piperidine Compound where X is 0 and R4 is -OH (3a-d).
The compounds of formula 2a-d are commercially available or can be prepared
by methods known in the art.
Compound 1 can be obtained by reacting 4 with an isocyanate as shown below
in scheme 1.2:
Scheme 1.2
0
On
3--(R36
)¨(R3)m 1) Ar,-NCO
N
2) 4N HC1 0 NH
Ar2
4 1
where R3, and m are as defined above and R is Ar2.
Compound 4 (20mmol) in chloroform is added to a solution of an isocyanate of
formula R-NCO in chloroform (30mL) at about 25 C. The resultant reaction
mixture is
stirred for about 3 h at about 25 C then concentrated under reduced pressure
to provide a
residue. The residue is suspended in THF (50mL) and 4N HC1 (50mL) is added to
the
resulting solution. The reaction mixture allowed to stir for about 12h. The
reaction
mixture is then poured into water (200mL), and the pH is adjusted to 10 or
greater with
aqueous potassium carbonate base. The resulting solution is extracted with
ethyl acetate
and the ethyl acetate layers are combined, dried (MgSO4) and concentrated
under
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reduced pressure to provide a residue that can be chromatographed using flash
chromatography on a silica gel column eluted with ethyl acetate/hexane
(gradient elution
from 30:70 to 70:30) to provide compound 1.
Isocyanates of formula Ar,-NCO are commercially available or are can be
prepared by reacting an amine Ar2NH2 with phosgene according to known methods
(See,
e.g., H. Eckert and B. Foster, Angew. Chem. Mt. Ed. Engl., 26, 894 (1987); H.
Eckert,
Ger. Offen. DE 3 440 141; Chem. Abstr. 106, 4294d (1987); and L. Contarca et
al.,
Synthesis, 553-576 (1996). For example, an amine Ar2NH2 can be reacted with
triphosgene as shown below.
Triphosgene
DCM
R-NH, ________________________________________ R-NCO
Typically a solution of triphosgene (about 0.3 equivalents or 0.3eq.) in DCM
(about 0.3M) is slowly added to a stirred solution of the amine (about 1.0eq.)
in DCM
(about 0.3M) at about 25 C. The reaction mixture is then stirred at about 25 C
for about
10 min. and the temperature is raised to about 70 C. After stirring at 70 C
for 3h., the
reaction mixture is cooled to 25 C, filtered, and the filtrate is concentrated
to provide the
isocyanate.
Cyclic acetals of formula 4 are commercially available or can be prepared by
methods known in the art.
The Piperidine Compounds where X is 0 and R4 is -OH can also be obtained by
the illustrative method shown below in schemes 1.3 and 1.4:
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Scheme 1.3
(R2 )6"----1N
0 \ /
OH
no , (R2)n
.\'' +I N t-butyl lithium / -78 C Ri
)¨(R3
Ri
=
N/ THF
N
1 1
P L NP
2a 6a
(R2 )p-"N
/
Ni01-1
(R2)pi
1 t-butyl lithium / -78 C R1
5 + Ri N THF 3m)
1
L NP
2b 6b
1\1===\
(R2)-. N
(R2)p .N \ 1 OH
5 + I IR1
N t-butyl lithium / -78 C ¨(R3)ni
R1 N)
THF
L 1
NP
2c 6c
N
(R2),,.
.. =N
\ /
OH
(R2 )p \
5 + -\N
R
I I Ri
¨1
N t-butyl lithium / -78% ( 3)rnN
R1 THF 1
L = NP
2d 6d
5 where RI,
R2, R3, n, m, and p are as defined above, L is a halogen, and NP is a nitrogen
protecting group (see, for example, T.W. Greene et al., Protective Groups in
Organic
Synthesis 494-653 (3d ed. 1999).
To a solution of t-BuLi (1.7M in heptane, 18.4mL, 31.3mmol) or n-BuLi (1.6M
in heptane, 19.5mL, 31.3mmol) in ether (30mL) is added dropwise a solution of
a
compound of formula 2a-d (31.3mmol) in ether (20mL) at -78 C under a nitrogen
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atmosphere. The resulting solution is stirred at -78 C for about 1 hour. To
the resulting
solution is added dropwise a compound of formula 5 (25.0mmol) dissolved in
ether
(20mL) at -78 C and the resulting mixture is allowed to stir at about -50 C
for 3 h. The
reaction mixture is then quenched with aqueous NH4C1 at 0 C and the reaction
mixture
is extracted with ether. The organic portions are combined, dried (Na2SO4),
and
concentrated under reduced pressure to provide a residue that can be
chromatographed
using flash chromatography on a silica gel column eluted with ethyl
acetate/hexane
(gradient elution 30/70 to 70/30) to provide a compound of formula 6a-d. The
nitrogen
protecting group is then removed to provide a compound of formula 7a-d,
respectively.
The compound of formula 7a-d is then reacted with an isocyanate of formula R-
NCO to
provide the compound of formula 3a-d, as shown below in scheme 1.4:
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Scheme 1.4
(R2)6----r."-\N
\ OH Ar,-NCO
____________________________________________________ Piperidine
R1 ¨ Compound 3a
)(R3)m
7a
N
Ar,-NCO
Piperidine
R1
)¨(R36 Compound 3b
7b
(R2)-NN
/ OH Ar7-NCO
____________________________________________________ Piperidine
R1
)¨(R3)rn Compound 3c
7c
,--N
µN
\ OH Ar,-NCO
Piperidine
R1 Compound 3d
7d
where Ar2, RI, R2, R3, n, m, and p are as defined above.
To a solution of a compound of formula 7a-d (Immo') in DCM (1mL) is added
dropwise a solution of isocyanate Ar2-NCO (Immo]) in DCM (1mL) at the about 25
C.
The resultant mixture is allowed to stir at 25 C for 3h and concentrated under
reduced
pressure to provide a residue that can be chromatographed using a silica gel
column
eluted with ethyl acetate/hexane (gradient elution 10/90 to 70/30) to provide
a
compound of formula 3a-d.
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A compound of formula 5 is commercially available or can be prepared by
protecting the nitrogen atom of a compound of formula 8, shown below:
0
,0
l"3/rn
8
Compounds of formula 8 are commercially available or can be prepared by
methods known in the art.
Any nitrogen protecting group known in the art can be used to protect the
nitrogen atom in the compound of formula 8. Suitable protecting groups are
described
in T.W. Greene et al., Protective Groups in Organic Synthesis, 494-653 (3d ed.
1999).
Isocyanates of formula Ar,-NCO are commercially available or can be prepared
as
described above.
5.5.1.2 Methods for Making Piperidine Compounds where X is S and
R4 is ¨OH
The Piperidine Compound where X is S and R.4 is -OH can be obtained by a
method analogous to that described above in Scheme 1.1 to provide the
Piperidine
Compounds where X is 0 and R4 is -OH (3a-d) except that a compound of formula
9,
shown below,
0
) (R3)m
SNH
Ar2
9
where R3 and rn are as defined above, is used in place of compound 1.
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The compound of formula 9 can be obtained by a method analogous to that
described above in Scheme 1.2 to provide 1 except that an isothiocyanate of
formula
Ar,-NCS is used in place of the isocyanate An-NCO.
Isothiocyanates are commercially available or can be prepared by reacting an
amine of formula ArNH, with thiophosgene as shown in the scheme below (See,
e.g.,
Tett. Lett., 41(37), 7207-7209 (2000); Org. Prep. Proced., Int., 23(6), 729-
734 (1991); J.
Heterocycle Chem., 28(4), 1091-1097 (1991);]. Fluorine Chem., 41(3), 303-310
(1988);
and Tett. Lth., 42(32), 5414-5416 (2001).
C(S)C1
Any-NH, 2 Ar -NCS
Alternatively, isothiocyanates of formula Ar)-NCS can be prepared by reacting
an amine of formula Ar2\11-12 with carbon disulfide in the presence of
triethylamine
(TEA) in THF, followed by reaction with hydrogen peroxide and hydrochloric
acid in
water as shown in the scheme below (See, e.g.,]. Org. Chem., 62(13), 4539-4540
(1997)).
1. TEA, THF, CS,
2. H20,
3. HC1, Water
Ary-NH, _________________________________________ Ary-NCS
The Piperidine Compound where X is S and R4 is -OH can be obtained by a
method analogous to that described above in Schemes 1.3 and 1.4 to provide the
Piperidine Compounds where X is 0 and R4 is -OH (3a-d) except that an
isothiocyanate
of formula Ar2-NCS is used in place of the isocyanate of formula Ar2-NCO.
5.5.1.3 Methods for Making Piperidine Compounds where X is N-CN and R4
is ¨OH
The Piperidine Compound where X is N-CN and R4 is -OH can be obtained as
shown below in scheme 1.5:
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Scheme 1.5
Ari OH
Ari OH
rJ
Ar2NH, y(R3)rn
NC¨N 0
NC¨N NH
Ar2
Piperidine
Compound
5 where Ari, Ar,), R3 and m are as defined above.
A compound of formula 10 is reacted with an amine of formula Ar2-NH2 in an
aprotic organic solvent such as diethyl ether, di-n-propyl ether, THF, DCM, or
toluene at
a temperature of from about 25 C to about the reflux temperature of the
solvent for a
period of from about 0.5 h to about 24 h to provide the Piperidine Compound
where X is
10 N-CN and R4 is -OH. In one embodiment, the aprotic organic solvent is di-
n-propyl
ether. In another embodiment, a reaction mixture of di-n-propyl ether, a
compound of
formula 10 and the amine of formula Ar,-Nfl, is heated at a temperature of
about 700 to
about 80 C. In another embodiment, the reaction mixture of di-n-propyl ether,
a
compound of formula 10 and the amine of formula An-NH, is heated at a
temperature of
about 75 C for about 12h.
The compound of formula 10 can be obtained as shown below in scheme 1.6:
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Scheme 1.6
OH
,CN Ar)1
7a-d + 0 0
NC¨N 0
35 401
5
where Ari is defined above for the Piperidine Compounds.
A compound of formula 7a-d is reacted with diphenyl cyanocarbonimidate 35
(commercially available from Sigma-Aldrich, St. Louis, MO) in an aprotic
solvent such
as diethyl ether, di-n-propyl ether, THF, DCM, or toluene to provide the
compound of
10 formula 10. In one embodiment, the aprotic solvent is DCM and the
reaction mixture of
the compound of formula 7a-d and diphenyl cyanocarbonimidate 35 is allowed to
react
at about 25 C. In another embodiment, the aprotic solvent is toluene and the
reaction
mixture of the compound of formula 7a-d and diphenyl cyanocarbonimidate 35 is
allowed to react at about 110 C. The compound of formula 7a-d and diphenyl
cyanocarbonimidate 35 is typically allowed to react for a period of about 0.5
h to about
24 h. Typically the compound of formula 10 is used without further
purification.
The compounds of formula 7a-d can be obtained as described above in section
5.5.1.1.
5.5.1.4 Methods for Making Piperidine Compounds where X is N-OH and
R4 is ¨OH
The Piperidine Compound where X is N-OH and R4 is -OH can be prepared by a
method analogous to that described above in Scheme 1.1 to provide the
Piperidine
Compounds where X is 0 and R4 is -OH (3a-d) except that a compound of formula
11,
shown below,
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0
T( R3)m
PO¨N NH
11
where R3 and m are as defined above, R is Ar2, and P is an oxygen/hydroxyl
protecting
group, is used in place of compound 1 followed by removal of the
oxygen/hydroxyl
protecting group.
The compound of formula 11 can be obtained as shown below in scheme 1.7:
Scheme 1.7
00 0
,
)(1 Protecting
m3)rn (R3)m group 7(R3)n,
N2
Ethanol 80 C
H3C¨S N
HO¨N NH OP¨O¨N NH
12 13 11
where R3 and m are as defined above, R is Ar2, and OP is an oxygen/hydroxyl
protecting
group.
A compound of formula 12 (about 0.3mmol) is reacted with hydroxylamine (50
weight percent in water, about 5.8mmol) in about 1.5mL of ethanol with
stirring at a
temperature of about 80 C for about 2 h. The mixture is then concentrated
under,
reduced pressure to provide a compound of formula 13. The hydroxyl group of
the
compound of formula 13 is then protected using an oxygen/hydroxyl protecting
group to
provide the compound of formula 11. An oxygen/hydroxyl protecting group known
in
the art can be used to protect the oxygen atom in the compound of formula 13.
Suitable
oxygen/hydroxyl protecting groups are disclosed in T.W. Greene et at.,
Protective
Groups in Organic Synthesis 17-200 (3d ed. 1999). In one embodiment, the
compound
of formula 11 is further treated using column chromatography or
recrystallized.
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The compound of formula 12 can be obtained as shown below in scheme 1.8:
Scheme 1.8
0 0
(R3)m
CH3I
TEA
NH
H3C¨S N
9 12
where R3 and m are as defined above and R is Ar2.
A solution of a compound of formula 9 (about 0.6mmol), obtained as described
above, in DCM is reacted with iodomethane (about 0.9mmol) in about 3mL of
tetrahydrofiiran with stirring at about 25 C for about 12 h. Excess
iodomethane is
removed from the mixture under reduced pressure. A solution of triethylamine
(about
1.74mmol) in about 2.5mL of ethyl acetate is then added to the mixture and the
mixture
is allowed to stir for about 2 h. The mixture is then concentrated under
reduced pressure
to provide the compound of formula 12 that can then be further treated if
desired. In one
embodiment, the compound of formula 12 is further treated using column
chromatography or recrystallization.
5.5.1.5 Methods for Making Piperidine Compounds where X is N-01110 and
R4 is ¨OH
The Piperidine Compound where X is N-ORio and R4 is -OH can be obtained by
a method analogous to that described above in Scheme 1.1 to provide the
Piperidine
Compounds where X is 0 and R4 is -OH (3a-d) except that a compound of formula
14,
shown below,
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0
3-(R3)m
R100¨N NH
14
where R3,Rio and m are as defined above and R is Ar2 is used in place of
compound 1.
The compound of formula 14 can be prepared by reacting the compound of
formula 13, obtained as described above in Scheme 1.7, with L-(C1-C4)alkyl,
where L is
-I, -Br, -Cl, or -F in the presence of sodium hydride in DMF at about 25 C. In
one
embodiment, L is -I or ¨Br.
5.5.1.6 Methods for Making Piperidine Compounds where R1 is a Group
Other Than ¨OH
The Piperidine Compounds where R4 is -halo, -0CF3, -(C1C6)alkyl, -CH2OH,
-CH2C1, -CH2Br, -CH2I, -CH2F, -CH(halo)2, -CF3, -OR o, -SR 10, -COOH, -COOR o,
-C(0)R,0, -C(0)H, -0C(0)R10, -0C(0)NHR 10, -NHC(0)R13, -S02R10, -CON(R13)2 or
-NO2 can be obtained from the Piperidine Compounds where R4 is -OH.
The Piperidine Compounds where R4 is -F can be obtained by reacting a
Piperidine Compound where R4 is -OH with fluorinating reagents such as DAST,
Deoxo-Fluor, SF4, HF, KF, CsF, Yarovenko's reagent, Ishikawa's reagent,
according to
the procedure described in M. Schlosser et al., Tetrahedron 52(24):8257-8262
(1996).
The Piperidine Compounds where R4 is -Cl can be obtained by reacting a
Piperidine Compound where R4 is -OH with SOC12 or PC15 according to the
procedure
described in]. Amer. Chem. Soc. 120(4):673-679 (1998) or with CH3C0C1
according to
the procedure described in Tett. Lett. 41(47):9037-9042 (2000).
The Piperidine Compounds where R4 is -Br can be obtained by reacting a
Piperidine Compound where R4 is -OH with pyridine and SOBr2 according to the
procedure described in J. Organometallic Chemistry 627(2):179-88 (2001) or by
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reacting a Piperidine Compound where R4 is -OH with pyridine and PPh3/Br2
according
to the procedure described in J. Amer. Chem. Soc. 112 (9):3607-14 (1990).
The Piperidine Compounds where R4 is -I can be obtained by reacting a
Piperidine Compound where R4 is -OH with HI in acetic anhydride according to
the
procedure described in J. Amer. Chem, Soc. 87(3):539-542 (1965).
The Piperidine Compounds where R4 is -CH3 can be obtained by reacting a
Piperidine Compound where R4 is -OH with PC15 and CH3TiCI3 according to the
procedure described in Angewandte ChenUe, 92(11), 933-4 (1980).
The Piperidine Compounds where R4 is -(CI-C6)alkyl can be obtained by
reacting a Piperidine Compound where R4 is -OH with p-toluenesulfonic acid in
toluene
followed by n-butyl lithium and X-(Ci-C6)alkyl, where X is a halogen,
according to the
procedure described in Charles J. Barnett, eta!, J. Org. Chem., 54(20) 4795-
4800 (1989)
followed by hydrogenating the product according to the procedure described in
Thomas
E. D'Ambra eta!, J. Org. Chem., 54(23) 5632-5 (1989) as described below.
1) p-Ts0H/Toluene, reflux 0 Pd/H,
o
OH _______________________________________
R4
2) n-BuLi/THF, R4X
CS
NP NP NP
The Piperidine Compounds where R4 is -CH2OH can be obtained by reacting a
Piperidine Compound where R4 is -COOH with LiA1H4 according to procedures
known
in the art. The Piperidine Compounds where R4 is -CH2OH can be obtained by
reacting
a Piperidine Compound where R4 is -C(0)H with NaBH4 according to procedures
known in the art.
The Piperidine Compounds where R4 is -COOH can be obtained by reacting a
Piperidine Compound where R4 is -CN with KOH according to procedures known in
the
art.
The Piperidine Compounds where R4 is -CN can be obtained by reacting a
Piperidine Compound where R4 is -OH with KCN and SOCl2 according to the
procedure
described in Arm.yanskii Khimicheskii Zhurnal. 30(9):723-727 (1977).
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The Piperidine Compounds where R4 is -C(0)H can be obtained by reacting a
Piperidine Compound where R4 is -CN with di-iso-butylaluminum hydride (DIBAL-
H)
according to procedures known in the art.
The Piperidine Compounds where R4 is -0CF3 can be obtained by reacting a
Piperidine Compound where R4 is -OH with CS?; methyl idodide; and
bromosuccinimide and pyridine/HF in DCM according to the procedure described
in
Chemical Communications (Cambridge) 3:309-310 (1997) or Bulletin of the
Chemical
Society of Japan, 73(2):471-484 (2000).
The Piperidine Compounds where R4 is -CH2C1 can be obtained by reacting a
Piperidine Compound where R4 is -CH,OH, obtained as described above, with PC15
according to the procedure described in J. Amer. Chem. Soc., 120(4):673-679
(1998).
The Piperidine Compounds where R4 is -CH?Br can be obtained by reacting a
Piperidine Compound where R4 is -CH20H, obtained as described above, with
SOBr2
according to the procedure described in J. Organoinet. Chem., 627(2):179-188
(2001) or
with PPh3/Br2 according to the procedure described in I Amer. Chem. Soc.,
112(9):3607-3614 (1990).
The Piperidine Compounds where R4 is -CH2F can be obtained by reacting a
Piperidine Compound where R4 is -C1-120H, obtained as described above, with 1
eq. of
DAST according to the procedure described in M. Schlosser et al., Tetrahedron
52(24):8257-8262 (1996) and Organic Letters. 3(17):2713-2715 (2001).
The Piperidine Compounds where R4 is -CH2I can be obtained by reacting a
Piperidine Compound where R4 is -CH2OH, obtained as described above, with
PP113/12
according to the procedure described in Organic Process Research and
Development
6(2):190-191 (2002).
The Piperidine Compounds where R4 is -CH(halo)2 can be obtained by reacting a
Piperidine Compound where R4 is -C(0)H, obtained as described above, with
(F3CSO2)20 followed by Mg(halo)2 in CS2 according to the procedure described
in
Synthesis 12:1076-1078 (1986).
The Piperidine Compounds where R4 is -CHF2 can also be obtained by reacting a
Piperidine Compound where R4 is -C(0)H, obtained as described above, with 2eg.
of
DAST according to the procedure described in M. Schlosser et al., Tetrahedron
52(24):8257-8262 (1996) and Organic Letters. 3(17):2713-2715 (2001).
The Piperidine Compounds where R4 is -CF3 can be obtained by reacting a
Piperidine Compound where R4 is -C(0)H, obtained as described above, with
copper (I)
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iodide and sodium trifluoroacetate according to the procedure described in
U.S. Patent
No. 4,866,197 to Bauman.
The Piperidine Compounds where R4 is -0R10 can be obtained by reacting a
Piperidine Compound where R4 is -OH, obtained as described above, with R10-X
where
X is a halogen in the presence of NaOH according to the procedure described in
European Journal of Medicinal Chemistry 24(4):391-396 (1989).
The Piperidine Compounds where R4 is -SRI3 can be obtained by reacting a
Piperidine Compound where R4 is -OH, obtained as described above, with R13-SH
according to the procedure described in U.S. Patent No. 4,409,229 to Ong et
al. or
Journal of Medicinal Chemistry 24(1):74-79 (1981).
The Piperidine Compounds where R4 is -COORio can be obtained by esterifying
a Piperidine Compound where R4 is -COOH, obtained as described above, with R10-
0H.
Methods to esterify carboxylic acids are known in the art.
The Piperidine Compounds where R4 is -0C(0)R10 can be obtained by reacting a
Piperidine Compound where R.4 is -OH, obtained as described above, with
R10C(0)C1
according to the procedure described in European Journal of Medicinal
Chemistry
24(4):391-396 (1989). The acid chlorides, R10C(0)C1, can be prepared from the
corresponding carboxylic acid, RioCOOH, using procedures known in the art.
The Piperidine Compounds where R4 is -NHC(0)R13 can be obtained by reacting
a Piperidine Compound where R4 is -OH with RioCN in the presence of H2SO4
followed
by 1(2CO3 in DCM as described in Bioorganic and Medicinal Chemistry Letters
10(17):2001-2014 (2000).
The Piperidine Compounds where R4 is -0C(0)NR2 can be obtained by reacting
a Piperidine Compound where R4 is -OH with Cl3CCONCO in DCM at 0 C with
stirring
for about 2 h and then adding to the resulting mixture K2CO3 in methanol-water
and
allowing the resulting mixture to stir for about 4 h at 0 C and about 2 h at
about 25 C
according to the procedure described in Christopher P. Holmes et al, J. Org.
Chem.,
54(1):98-108 (1989).
The Piperidine Compounds where R4 is -0C(0)NHR10 can be obtained by
reacting a Piperidine Compound where R4 is -OH with an isocyanate of formula
RioNCO in refluxing THF for about 24 h at about 25 C according to the
procedure
described in Andre Hallot et al, J. Med. Chem., 29(3):369-375 (1986).
The Piperidine Compounds where R4 is -5O2R10, -NO2, -CN, -CORI , -COORio,
and CON(R13)2 can be prepared by the illustrative methods described below.
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A compound of formula 15 is reacted with a compound of formula 16a-d in the
presence of a base according to the procedure described in Journal of
Heterocycle
Chemist-1y, 23(1):73-75 (1986) or Organic Chemistry and Procedures
International
28(4):478-480 (1996) to provide a compound of formula 17a-d, as described
below in
scheme 1.9:
Scheme 1.9
(R2)ri
CI
base
(R3)m
+ R1
NP
16a NP
17a
N
(R2)p
N\ base
R3
R1N
15 +
NP
16b
17b
(R2 )/3\1 N
RDp y
base
I I R1
¨(R3)
15 + Ri N)
16c NP
17c
(R2)n\::::N\N
(R2)P\ y
N
I base
15 + RN
R1
N-.(R3)m
16d NP
17d
where RI, R2, R3, n, m, and p are as defined above; Y is -S02R10, -NO2, -CN, -
CORR),
10 -COORio, or CON(R13)2; and NP is a nitrogen protecting group.
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The nitrogen protecting group is then removed from the compound of formula
17a-d to provide a compound of formula 18a-d. Any nitrogen protecting group
known
in the art can be used to protect the nitrogen in the compound of formula 15.
To provide the Piperidine compounds of formula I where X is 0 and R4 is
-S02R10, -NO2, -CN, -CORio, -COORio, or CON(R13)2, the compound of formula 18a-
d
is then reacted with an isocyanate of formula R-NCO according to a procedure
analogous to that described above in scheme 1.4 and described below in Scheme
1.10:
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Scheme 1.10
(RA \----- iN
(R2)n\---- N y
\ y
(R3)rn R-NCO '(1R3)1-n
N2
HI
0' NH
18a
N (R2)p<%\N
Ri
R1 + R-NCO ¨(R3)n,
N)
0 NH
18b
(R2)p\N (R2)p.\IN
\I \ I y
\ y
R1 )¨
+ R-NCO Ri (R3)rn
N2
0NH
18c
(R2)r)/ µ,N1
y
y
)¨(R3)m
=(Ra)m + R-NCO
HI
NH
18d
where RI, R2, R3, n, m, and p are as defined above; Y is -S02R10, -NO2, -CORI
, or
-CON(R13)2; and R is Ar-,
A compound of formula 18a-d is reacted with a compound of formula R-NCO
according to a procedure analogous to that described above in Scheme 1.4.
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To provide the Piperidine Compounds where X is S and R4 is -S02R10, -NO2,
-CN, -CORI , -COORio, or CON(R13)2, the compound of formula 18a-d is reacted
with
an isothiocyanate of formula R-NCS according to a procedure analogous to that
described above in Section 5.5.1.2.
To provide the Piperidine Compounds where X is N-CN and R4 is -S0/R101
-NO2, -CN, -CORR), -COORio, or CON(R13)2, the compound of formula 18a-d is
reacted
with diphenyl cyanocarbonimidate 35 and then an amine of formula R-NR2
according to
a procedure analogous to that described above in Section 5.5.1.3.
To provide the Piperidine Compounds where X is N-OH and R4 is -SO2R103
-NO2, -CN, -CORI , -COORio, or CON(R13)2, the Piperidine Compound where X is S
and R4 is -SO2R10, -CN, -CORio, -COORio, and CON(R13)2 is reacted with
methyl
iodide according to a procedure analogous to that described above in scheme
1.8 to
provide a compound of formula 19,
AriX
) (R3)m
H3C¨S N
19
where Ari, R3, m, and Y are as defined above and R is Ar,.
The compound of formula 19 is then reacted with hydroxylamine in ethanol
according to a procedure analogous to that described above in Scheme 1.8 to
provide the
Piperidine Compounds where X is N-OH and R4 is -SO2RI0, -NO2, -CN,
-COORio, or CON(R13)2.
To provide the Piperidine Compounds where X is N-ORio and R4 is -5O2R10,
-CN, -CORK), -COORio, or CON(R13)2, the Piperidine Compound where X is
NOH and R4 is -SO,Rio, -CN, -
CORI , -COORio, and CON(R13)2 is reacted with
X-(C1-C4)alkyl, where X is -I, -Br, or -F in the presence of triethylamine
according
to a procedure analogous to that described above in Section 5.5.1.6.
The compound of formula 15 is commercially available or can be prepared by
methods known in the art.
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The compounds of formula 16a-d where Y is -S02R10 can be obtained by
reacting a compound of formula 16a-d, where Y is a halogen, with R10S0214
according
to the procedure described in J. Org. Chem. 67(13):4387-4391 (2002) or
international
publication no. WO 02/48098.
The compounds of formula 16a-d where Y is -CN can be obtained by reacting a
compound of fommla 16a-d, where Y is a halogen, with potassium cyanide
according to
the procedure described in Farmaco 45(9):945-953 (1990).
The compounds of formula 16a-d where Y is -COORio can be obtained by
reacting a compound of formula 16a-d, where Y is a halogen, with (a) potassium
cyanide, (b) water, and (c) RI00H and SO2C1 according to the procedure
described in
Fartnaco 45(9):945-953 (1990).
The compounds of formula 16a-d where Y is -CORI can be obtained by
reacting a compound of formula 16a-d, where Y is a halogen, with R10C(0)H and
trimethylsilyl cyanide according to the procedure described in international
publication
no. WO 01/81333.
The compounds of formula 16a-d where Y is -CON(R13)2 can be obtained by
reacting a compound of formula 16a-d, where Y is a halogen, with (a) potassium
cyanide, (b) water, and (c) NH(R13)2 and SO2C1 according to the procedure
described in
Farmaco 45(9):945-953 (1990).
The compounds of formula 16a-d where Y is -NO2 can be obtained by reacting a
compound of formula 2a-d where X is -CH3 with NaNH2 in liquid NH3 followed by
CH3CH2CH3-0NO2 at a temperature of less than -33 C to provide a nitronate that
is then
reacted under acidic condition to provide the compound of formula 16a-d where
Y is
-NO2 according to the procedure described in H. Feuer et al., J. Am. Chem.
Soc.
91(7):1856-1857 (1969) and as described in scheme 1.11 below, where RI, R2, n
and p
are as defined above.
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Scheme 1.11
(R2)n.<.(R2)(31\1 (R2)p\
(R2) N
I N
R1
Ri N
CH3 CH3 CH3 CH3
2a 2b 2c 2d
1) NaNFI, / liquid NH3
2) CH3C1-1,CH2-0N07, <-33 C
3) H
(R2)(R2) (R2)p,.N (R2)p,\IN
,=-=\
I N
Ri
NO2 NO2 NO2 NO2
The compounds of formula 16a-d where Y is -halo are commercially available or
can be prepared by methods known in the art.
Certain Piperidine Compounds can have one or more asymmetric centers and
therefore exist in different enantiomeric and diastereomeric forms. A
Piperidine
Compound can be in the form of an optical isomer or a diastereomer.
Accordingly, the
invention encompasses Piperidine Compounds and their uses as described herein
in the
form of their optical isomers, diastereomers, and mixtures thereof, including
a racemic
mixture. Optical isomers of the Piperidine Compounds can be obtained by known
techniques such as chiral chromatography or formation of diastereomeric salts
from an
optically active acid or base.
In addition, one or more hydrogen, carbon or other atoms of a Piperidine
Compound can be replaced by an isotope of the hydrogen, carbon or other atoms.
Such
compounds, which are encompassed by the invention, are useful as research and
diagnostic tools in metabolism pharmacokinetic studies and in binding assays.
5.5.1.7 Methods for Installing R2 Groups on Ari When R2 is Q
The conversion of a halide, L to a vinyl group via a Suzuki cross-coupling
reaction is exemplified in scheme 1.12 below, where RI, R), R4 and p are as
defined
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above, L is defined as ¨halo, and P is a nitrogen protecting group known in
the art.
While this example demonstrates the conversion when L is in the 5-position of
the
pyridyl ring of 20, the transformation can be carried out when L is in other
positions on
the aryl ring as well. Moreover, the same technique can be used when Ari. is
another
pyridyl ring, pyrimidinyl, pyrazinyl or pyridazinyl ring.
Scheme 1.12
II
2 N N
/ /
R4 _________________________________________ )Mir R4
Pd(DPPF),C1, , R1
(R3)r-n DMF, 100 C, 14h N)
¨(R3)m
NP NP
20 21
To a degassed DMF solution of compound 20 (1.6 mmol) in a 100 mL round
bottom flask, is added CsF (3.2 mmol), di-n-butyl vinyl boronic ester (0.388
mL, 1.76
mmol) and palladium diphenylphosphinoferrocene dichloride (Pd(DPPF)2C12, 0.128
mmol). The resulting mixture is stirred at 100 C for 14 hr, then cooled to a
temperature
of about 25 C and diluted with 100 mL ethyl acetate, which was washed with
brine (3 x
50 mL). The organic layer was isolated, dried, and concentrated under reduced
pressure.
Silica gel column chromatography gives the product, 21.
Other techniques for the installation of the vinyl group are shown in schemes
1.13a and 1.13b. In scheme 1.13a, the first step involves the oxidation of a
benzylic
alcohol to an aldehyde. This is followed by a Wittig olefination, to yield the
vinyl
group. Once again, while this example demonstrates the conversion when the
starting
benzylic alcohol is in the 5-position of a pyridyl ring, similar conversions
can be carried
out at other positions. Moreover, the same technique can be used when Arr is
another
pyridyl ring, pyrimidinyl, pyrazinyl or pyridazinyl.
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Scheme 1.13a
CH2OH CHO
(R2)õ I (R2),
MnO,
CH2C12
N
22 23
CHO
(R2)nJ PPh3CH3Br (R2)n
(t-BuO)K
Benzene/THF
R1
23 24
To a 500 mL round-bottom flask, manganese oxide (0.50 mol) is added to a
solution of 22 (50.0 mmol) in anhydrous CH2CF2 (150 mL). The resulting mixture
is
stirred at a temperature of about 25 C for 48 h and then the reaction mixture
is filtered
through CELITE and concentrated. The resulting mixture is chromatographed by
silica
gel column chromatography eluting with a gradient of ethyl acetate (0%-
40%)/hexanes
to provide aldehyde 23.
To a cooled 0 C, stirred slurry of methyltriphenylphosphonium bromide (10.0 g)
in toluene (200 mL) is added potassium t-butoxide (3.07 g) portionwise to
produce a
yellow slurry. After 1 hr, the reaction mixture is cooled to -20 C, and 23
(22.72 mmol)
dissolved in tetrahydrofiiran (6 mL) is added dropwise to produce a purple
colored
slurry. The reaction mixture is heated to 0 C and stirred for additional 1 hr.
Then the
reaction mixture is treated with saturated aqueous brine (150 mL) and diluted
with ethyl
acetate (200 mL). The resulting organic layer is washed with brine, dried over
anhydrous sodium sulfate and concentrated under reduced pressure. The
resulting
product is chromatographed by silica gel column chromatography column, eluting
with a
gradient of ethyl acetate (0%-10%)/hexanes to provide product 24.
In scheme 1.13b, the first step involves the reduction of a benzylic ketone to
a
hydroxyl. This is followed by a dehydration reaction to yield the vinyl group.
Once
again, while this example demonstrates the conversion when the starting
benzylic ketone
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is in the 5-position of a pyridyl ring, similar conversions can be carried out
at other
positions. Moreover, the same technique can be used when Ar, is another
pyridyl ring,
pyrimidinyl, pyrazinyl or pyridazinyl.
Scheme 1.13b
HO
(R2)n (R2)ri
Na131-14
Ri
23 23a
HO
uso
(R2)n
(R2)n
0=s=0 /\
OH
RI
Ri
24
23a
To a well-stirred suspension of 23 (665 g, 3.5 mol) in methanol (3.5L) at 0 C
is
added sodium borohydride (66.21 g, 1.75 mol) portionwise at a rate such that
the
reaction mixture temperature does not exceed 5 C. After the addition is
complete, the
reaction mixture is warmed to a temperature of about 25 C and stirred an
additional 1 h.
The reaction mixture is concentrated under reduced pressure and the residue
mixed with
2L diethyl ether and 2L IN HC1. The layers are separated and the aqueous layer
extracted twice with diethyl ether (250 mL for each extraction). The organic
portions
are combined, dried (MgSO4), and concentrated under reduced pressure to
provide 23a.
To a solution of 23a (311 g, 1.62 mol) in chlorobenzene (3 L) is added p-
toluene
sulfonic acid (431 g, 2.5 mol). The reaction mixture is heated to reflux,
about 140 C,
and water is removed concurrently. At the completion of the reaction, the
mixture is
concentrated under reduced pressure to about 500 mL, diluted with 2L of water,
and
extracted three times with ethyl acetate (1L for each extraction). The organic
portions
are combined, dried (Na2SO4), and concentrated under reduced pressure under
mild
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heating to provide a residue. The residue is added to 500 mL of methylene
chloride and
applied to the top of column packed with 2 kg silica eluted with a 0% to 10%
gradient of
ethyl acetate in hexane to provide 24.
Vinyl groups are highly versatile, because they are a synthetic handle that
can be
further modified. It is well known in synthetic organic chemistry that olefin
hydrolysis
yields a benzylic hydroxyl group, hydroboration gives a primary hydroxyl
group,
ozonolysis gives an aldehyde or ketone, oxidation gives a carboxylic acid,
olefin
metathesis extends the chain, and dihydroxylation gives a 1,2-diol. Many
additional
olefin functionalization techniques are available to those skilled in organic
synthesis.
Once functionalized, the group can undergo further transformations.
Exemplified in
scheme 1.14 is the vinyl group of 21 undergoing an asymmetric dihydroxylation.
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Scheme 1.14
(R2 N (R2 N
R4 AD-mix a 0, R4
t-BuOH/H20
Ri Ri
)¨(R 3)m R36
NP NP
21 25a
HO
(R2 N (R2 N
R4 AD-mix (3 R4
t-BuOH/H20
Ri Ri
)¨(R3)m (R3)m
NP NP
21 25b
HO
(R2 N (R2 N
R4 0s04, NMO R4
F1,0/Acetone R
)
R1 i
¨(R3)m
NP NP
21 25c
In a 100 mL round bottom flask, AD-mix a (0.5 g) is added to a mixture of
t-butanol and water (2mL/2mL) and the mixture is stirred at a temperature of
about 25 C
for 0.5 hr, and then cooled to 0 C. This solution is quickly poured into
another ice
chilled flask, which contains compound 21(0.41 mmol). The mixture is stirred
vigorously in an ice bath for 96 h, and then diluted with ethyl acetate (50
mL) and 2 mL
saturated Na2S205. The ethyl acetate layer is isolated, dried, and
concentrated under
reduced pressure with a rotary evaporator to provide 25a. The other
enantiomer, can be
synthesized by the reaction of 21 with AD-mix 13 to yield 25b. As demonstrated
in
scheme 1.14, the stereochemistry (R or S) of the resulting diol, is dependent
upon the
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chirality of the ligand used in the AD mix as described in Sharpless et al.,
J. Org, Chem.
57:2768-2771 (1992). AD-mix is composed of the following components: potassium
osmate (K20s02(OH)4), potassium ferricyanide (K3Fe(CN)6), potassium carbonate
(K2003), and the chiral ligands are shown in scheme 1.15.
Scheme 1.15
Ligand for AD-mix cc
NI N¨N
o o F
H H
Me0
OMe
N
Ligand for AD-mix 13:
N¨N
1:1 o o H
Me
OMe
N
The racemic diol, 25c, can be synthesized by methods known in the art, using
osmium tetroxide (0s04) and N-methyl morpholine N-oxide (NIVIO) in an aqueous
acetone solution,
5.5.2 Methods for Making Compounds of Formula I where W is C and the
Dashed Line is Present
The compounds of formula 1 where W is C and the dashed line is present, i.e.,
"Tetrahydropyridyl Compounds," can be made using conventional organic
synthesis or
by the following illustrative methods shown in the schemes below,
RECTIFIED SHEET (RULE 91) ISA/EP
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5.5.2.1 Methods for Making the Tetrahydropyridyl Compounds Where X
is 0
The Tetrahydropyridyl Compounds where X is 0 can be obtained by the
following illustrative method shown below in Schemes 2.1 and 2.2, where R3,
Ar2, and
m are as defined above.
Scheme 2.1
0 0-S02CF3
1. LiHMDS
,..)¨(R3)m
.N) --(R3)11-1
CI
N
NSO2CF3)2
OH
Ar2 26 ( Ar2
1 27
Referring to scheme 2.1 above, compound 1 (about 3.6mmol) is dissolved in
THF (100mL) and the resulting solution cooled to -78 C. To the cooled solution
is
added LiHMDS (8.75mmol) and the reaction mixture is stirred at -78 C for 2 h.
Compound 26 (about 3.6mmol, Sigma-Aldrich) is then added to the reaction
mixture
and the reaction mixture is stirred at -78 C for 2 h. The reaction mixture is
then allowed
to warm to 25 C and concentrated under reduced pressure to provide a compound
of
formula 27.
The compound of formula 27 is then reacted with a compound of formula 28a-d
to provide the Tetrahydropyridyl Compound where X is 0 as shown below in
scheme
2.2:
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Scheme 2.2
(R2)n
(RA L\N
I
27 +
..\' I Pd(PPh3)4 R1)..-
R(.N THE, reflux
ZnBr N
28a
0.----NH
1
Ar2
(R2)p\
N
(R2)p
)-1-...,,,N
N\ Ri
RiN Pd(PPh3)4
27 + ii.
THE, reflux
C¨J (R3)m
ZnBr N
28b
0----NH
1
Ar2
(R2)p N
(R2) " N
1-\'" "Ri
27 + I I
--yN Pd(PPh3)4 i.
R1 THE, reflux
0¨(R36
ZnBr N
28c
0-"--NH
1
Ar2
( \---=
(R2)p)\\ (R2)p\
Y
27 + i I ,JiN
R1 Pd(PPh3)4 R1
on
ZnBr THF, reflux
28d
N
0---;"---NH
1
Ar2
where RI, R2, R3, Ari, n, m, and p are as defined above.
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Pd(PP112)4 (0.11mmol) is dissolved in THF (about 50mL) and the compound of
formula 27 (about 2.2mmol) is added to the resulting solution followed by a
compound
of formula 28a-d (about 6,6mmol as a 0.5M solution in THF).
The reaction mixture is then heated for 1 h at the reflux temperature of the
solvent. The reaction mixture is allowed to cool to 25 C and concentrated
under reduced
pressure to provide the Tetrahydropyridyl Compound where X is O. The
Tetrahydropyridyl Compound where X is 0 can be further treated if desired. In
one
embodiment, the Tetrahydropyridyl Compound where X is 0 is chromatographed
using
silica gel column chromatography followed by trituration with ethyl acetate.
Where m =1, R3 is bonded to an sp3 carbon, and 27 is either racemic or a
mixture
of enantiomers, the resulting Tetrahydropyridyl Compound in scheme 2.2 will
also be
racemic or an enantiomeric mixture. If a single stereoisomer is desired, it is
possible to
use chiral separation techniques known in the art, such as chiral
chromatography or
chiral resolution, to isolate a single isomer.
Another technique that can be used to couple the tetrahydropyridyl group and
Ari is the Suzuki cross-coupling reaction. This is accomplished by a catalyst
mediated
reaction of 2a with the tetrahydropyridyl borane, 29 as exemplified in scheme
2,3 below.
While the reaction shown has Ari as a pyridyl group, the same technique can be
used
when Arr is a pyrazinyl (2b), pyrimidinyl (2c), pyridazinyl (2d) or other
pyrazinyl
rings.
Scheme 2,3
R2 n
0 \ N
R
R2 n
\Th.
Pd(PPhi),C17
(R3),õ K2CO3 )0- (R3),
Ri DME/Et01-1/H20
NI;')
N P
2a 29 30
A 150 mL sealed vessel is charged with 2a (3,37 mmol), 29 (4.04 mmol),
Pd(PPh3)2C12 (0.27 mmol), potassium carbonate (6.40 mmol), and a mixture of
DME/Et0H/H20 (8 mL/4 mL/8 mL). The resulting mixture is purged with nitrogen,
RECTIFIED SHEET (RULE 91) ISA/EP
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sealed, and heated at 90 C with a vigorous stirring. After 2 hrs, the reaction
mixture is
cooled to a temperature of about 25 C and diluted with Et0Ac (50 mL). The
organic
layer is washed with brine, dried (Na2SO4), and concentrated under reduced
pressure.
The residue is chromatographed by silica gel column chromatography with a
gradient of
ethyl acetate (0%-30%)/hexanes to provide product 30.
The boronate ester, 29 can be synthesized by the method demonstrated below in
scheme 2.4.
Scheme 2.4
(
0õ0
S02(CF2)3CF3 B-B
\O
¨(R ) ___________________________________________
N2 3 m DPPF (3mol%)
Pd(DPPF)7C12, KOAc, Dioxane
NP NP
85 C
29
Bis(pinacolato)diboron (333.6 mmol), diphenylphosphino ferrocene (9.1 mmol),
palladium diphenylphosphinoferrocene dichloride (1:1 complex with
dichloromethane)
(9.1 mmol), and potassium acetate (909.9 mmol) are suspended in dry dioxane
(900 mL)
under argon with mechanical stirring. 4-(Nonafluorobutane-1-sulfonyloxy)-3,6-
dihydro-
2H-pyridine-1-carboxylic acid tert-butyl ester (303.3 mmol) in dry dioxane
(500 mL) is
added and the mixture is heated to 85 C for 16 h. The mixture is cooled,
filtered
through CELITE, and the filter cake is washed with dichloromethane (2L). The
filtrate
is concentrated under reduced pressure to provide a black solid. This is
adsorbed onto
silica gel (250g) and applied to the head of a 4" silica gel column, and it is
then eluted
with hexanes (5L) followed by 20:1 hexanes:ethyl acetate, and finally ethyl
acetate
(10L) to yield 29.
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5.5.2.2 Methods for Making the TetrahydroPyridyl Compounds Where X
is S
The Tetrahydropyridyl Compounds where X is S can be obtained by methods
analogous to that described above in schemes 2.1 and 2,2 to provide the
Tetrahydropyridyl Compounds where X is 0, except that an isothiocyanate of
formula
Ar2-NCS is used in place of the isocyanate Ar2-NCO.
5.5.2.3 Methods for Making the Tetrahydropyridvl Compounds Where X is
N-CN
The Tetrahydropyridyl Compounds where X is N-CN can be obtained as shown
below in Schemes 2.5 and 2.6 where Ar2, R3, and m are as defined above.
Scheme 2.5
*". n
0\,,0
-1--(R3),
'Th 0
\N,
71 (R3)m
NC¨N.:7---L0 Ar2NH2). NI HC1/Acetic acid),
NC¨N---: H -
_
0
Ar2 NC¨NNH
Ar2
31 32 33
Cl¨c N--/ N(S020F)2 LEN/IDS
26
0¨S02CF3
Ns. )¨(R3)m
N
NC¨Nl=-:"LNH
I
Ar2
RECTIFIED SHEET (RULE 91) ISA/EP
__ .
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A ketal of formula 31 (about 14mmol) is reacted with an amine of formula Ar-
NH2 (about 14mrnol) in an aprotic organic solvent (about 7mL) such as diethyl
ether, di-
n-propyl ether, THF, DCM, or toluene at a temperature of from about 25 C to
about the
reflux temperature of the solvent for a period of from about 0.5 h to about 24
h. The
reaction mixture is then concentrated under reduced pressure to provide a
compound of
formula 32. In one embodiment, the aprotic organic solvent is di-n-propyl
ether, In
another embodiment, a reaction mixture of di-n-propyl ether, a compound of
formula 31
and the amine of formula Ar-NH2 is heated at a temperature of about 70 to
about 80 C.
The compound of formula 32 is then dissolved in THF (about 20mL). About 1N
HC1 in acetic acid (about 30mL) is added to the THF solution of the compound
of
formula 32 and the resulting mixture is heated at the reflux temperature of
the solvent.
Typically, the reaction mixture is heated at the reflux temperature of the
solvent for
about 3 h. The reaction mixture is then cooled and concentrated under reduced
pressure
to provide a residue that is dissolved in DCM. The DCM solution is then
extracted with
aqueous Na2CO3. The aqueous and organic layers are separated and the aqueous
layer is
extracted three times with DCM. The organic portions are combined, dried
(MgSO4),
and concentrated under reduced pressure to provide a compound of formula 33.
The
compound of formula 33 can be further treated if desired. In one embodiment,
the
compound of formula 33 is chromatographed using silica gel column
chromatography,
The compound of formula 33 (about 3,6mmol) is then dissolved in THF (about
100mL) and the resulting solution cooled to about -78 C. To the cooled
solution is
added LiHMDS (about 8.75mmol) and the reaction mixture is stirred at about -78
C for
abotit 2 h. A compound of formula 26 (about 3.6mmol, Sigma-Aldrich) is then
added to
the reaction mixture and the reaction mixture stirred at about -78 C for about
2 h. The
reaction mixture is then allowed to warm to about 25 C and concentrated under
reduced
pressure to provide a compound of formula 34.
The compound of formula 34 is then reacted with a compound of formula 28a-d
as shown below in scheme 2.6 below to provide the Tetrahydropyridyl Compound
where X is N-CN,
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Scheme 2.6
(RAI
(R2)n N
34 +
N Pd(PPh3)4
THF, reflux
0¨(R3)rn
ZnBr
28a NC\
N NH
Ar2
(R2)p,
N \
(R2)p
N\
34 +
Pd(PPh3)4
THF, reflux
0¨(R3)m
ZnBr
28b NC\
N NH
Ar2
(R2)p N
()\1
(R2)p N
I\ Pd(PPh3)4
34 +
N THF, reflux
0¨(R3)m
ZnBr
28c NC\
N NH
Ar2
(R2)p,\ (R2)p\N
34 + IN
R1 Pd(PPh3)4 R1
ZnBr THF, reflux
0¨(R3)m
28d
NC,
N NH
Ar2
where Ar2, RI, R2, R3, n, m, and p are as defined above.
Pd(PPh3)4 is dissolved in THF (about 50mL) and the compound of formula 34
(about 2.2n-imol) is added to the resulting mixture followed by a compound of
formula
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28a-d (about 6.6mmol a3 a 0.5M solution in THF). The reaction mixture is then
heated
for about 1 h at the reflux temperature of the solvent, The reaction mixture
is allowed to
cool to about 25 C and concentrated under reduced pressure to provide the
Tetrahydropyridyl Compound where X is N-CN. The Tetrahydropyridyl Compound
where X is N-CN can be further treated if desired, In one embodiment, the
Tetrahydropyridyl Compound where X is N-CN is chromatographed by silica gel
column chromatography.
Where m =1, R3 is bonded to an sp3 carbon, and 34 is either racemic or a
mixture
of enantiomers, the resulting Tetrahydropyridyl Compound in scheme 2.6 will
also be
racemie or an enantiomeric mixtures. If a single stereoisomer is desired, it
is possible to
use chiral separation techniques known in the art, such as chiral
chromatography or
chiral resolution, to isolate a single isomer.
The compound of formula 31 can be obtained as shown below in scheme 2,7.
Scheme 2,7
0\,,o
,CN
(R 3)m
(cs.,0
---0 0-
NC=-N
40,
35 4
31
where R3, and m are as defined above,
Compound 4 is reacted with diphenyl cyanocarbonimidate 35 (Sigma-Aldrich) in
an aprotic solvent such as diethyl ether, di-n-propyl ether, THF, DCM, or
toluene to
provide the compound of formula 31. In one embodiment, the aprotic solvent is
DCM
and the reaction mixture of compound 4 and diphenyl cyanocarbonimidate 35 is
allowed
to react at about 25 C. In another embodiment, the aprotic solvent is toluene
and the
reaction mixture of compound 4 and diphenyl cyanocarbonimidate 35 is allowed
to react
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at about 110 C. Compound 4 and diphenyl cyanocar'oonimidate 35 are typically
allowed
to react for a period of about 0.5 h to about 24 h. .
The compounds of formula 28a-d can be obtained as described above by
methods known in the art.
5.5.2.4 Methods for Making the Tetrahydropyridyl Compounds Where X
is N-011
The Tetrahydropyridyl Compounds where X is N-OH can be obtained in a
manner analogous to schemes 2.6 and 2.7 in section 5.4,23, which is shown in
scheme
2.8.
Scheme 2.8
(r\
)<
1.
0 ()) ArrNH2
3¨(Ra)m
2. HCl/Acetic acid
(R3)m
N H
1r2
37
36
0
0¨S02CF3
LiHMDS
N CL
31¨(R3)m _________________________________________________ 7¨(R36
P¨C)¨NNH SO F OP¨O¨NNH
Ar2
26 38 Ar
37 2
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(FROn (R2)rt
I\Th
R 1 Ri
I Pd(PP113)4 deprotect ..,,
38 .4. ""..NT, reflux
N7-(R3)H
j 3/m
Znar N-
28a OP¨O-NNH HO-NNH
i1
Ar2 Ar2
39a
(R2)p (R2)0µ
,)- N
Riõk, N
(R2)) R1 ,..,
N\Id
38 + 1 hi P (PPh3)4 0. ____ deprotect =
Ri ' " THT, reflux
n¨(R3)iy,
---(R3)rn
nEr N N
28b
OF¨O-N NH HO-NNH
Ar2 Ar2
39h
(RA, A (R2)ps.N.,
N
(R2)13,N,.., Ri RI ' N
38 + 1 I Pd(PPI13)4 deprotect
w w
RiVIN THF, reflux C)--(R3)rn
C12)¨(R3)rn
Br
;8c OP¨O-N . NH HON. Ni 1-i
1
,q2 Ar2
39c
(R2)P\N
OR2)P\--, .. N
''N Ri RI
38 T I ti Pd(PPh3)4 deprotect
Rir"- TI-IF,r r7N, -===
reflux L 'NI 9
¨(R3)m
ZnBr N
28d
OP-0--NNH HO¨N---LNH
i
Ar2 Ar2
39d
where Ar2, Ri, R2, R3, n, m, and p are as defined above and P is an
oxygen/hydroxyl
protecting group.
The method for obtaining the Tetrahydropyridyl Compounds where X is N-OH
as described above in scheme 2.8 is analogous to that described above in
Schemes 2.5
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and 2.6 to provide the Tetrahydropyridyl Compounds where X is N-CN except that
a
compound of formula 38 is used in place of the compound of formula 34.
The compound of formula 36 can be obtained as described below in scheme 2.9.
Scheme 2.9
0\,,0
N) N1120H 7(R3)m
N Ethanol, 800 C
HO¨N NH
k2 Ar2
40 41
7(Ra)m Protecting Group (Ra)rn
___________________________________________ Er
P¨C)¨N------L NH
Ar2
Ar2
41 36
where Ar2, R3, and m are as defined above and P is an oxygen/hydroxyl
protecting
group.
A compound of formula 40 (about 0.3mmol) is reacted with hydroxylamine (50
weight percent in water, about 5.8mmol) in about 1.5mL of ethanol with
stirring at a
temperature of about 80 C for about 2 h. The mixture is then concentrated
under
reduced pressure to provide a compound of formula 41. The hydroxyl group of
the
compound of formula 41 is then protected using an hydroxyl protecting group to
provide
the compound of formula 36. Any hydroxyl protecting group known in the art can
be
used to protect the hydroxyl group in the compound of formula 41. Suitable
hydroxyl
protecting groups and methods for their removal are disclosed in T.W. Greene
et al,
Protective Groups in Organic Synthesis 17-200 (3d ed. 1999).
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Where m =1, R3 is bonded to an sp3 carbon, and 38 is either racemic or a
mixture
of enantiomers, the resulting Tetrahydropyridyl Compound in scheme 2.8 will
also be
racemic or enantiomeric mixtures. If a single stereoisomer is desired, it is
possible to
use chiral separation techniques known in the art, such as chiral
chromatography or
chiral resolution, to isolate a single isomer.
The compound of formula 40 can be obtained as shown below in scheme 2.10.
Scheme 2.10
C)0
3¨(R3)m
CH3I
TEA
Ar2 Ethyl acetate
Ar2
42 40
where Ar2, R3, and m are as defined above.
A solution of a compound of formula 42 (about 0.6mmol), obtained as described
above in section 4.4.2.2, in DCM is reacted with iodomethane (about 0.9mmol)
in about
3mL of tetrahydrofuran with stirring at about 25 C for about 12 h. Excess
iodomethane
is removed from the mixture under reduced pressure. A solution of
triethylamine (about
1.74mmol) in about 2.5mL of ethyl acetate is then added to the mixture and the
mixture
is allowed to stir for about 2 h. The mixture is then concentrated under
reduced pressure
to provide the compound of formula 40 which can then be further treated if
desired. In
one embodiment, the compound of formula 40 is chromatographed using column
chromatography or recrystallized.
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5.5.2.5 Methods for Making the Tetrahydropyridyl Compounds Where X
is N-0R10
The Tetrahydropyridyl Compounds where X is N-ORio can be obtained by
reacting a Tetrahydropyridyl Compounds where X is N-OH, obtained as described
above in Scheme 2.8, with L-(C1-C4)alkyl, where L is -I, -Br, -Cl, or -F, in
the presence
of about 3 eq. of triethylamine in THF, with stirring at about 25 C for about
12 h or at
about 50 C for about 3 h. The reaction mixture is concentrated under reduced
pressure
to provide a residue. The residue is then chromatographed using silica gel
column
chromatography eluted with a gradient elution of from 100:0 hexane:ethyl
acetate to
25:75 hexane:ethyl acetate to provide the Tetrahydropyridyl Compounds where X
is N-
Oltio. In one embodiment, L is -I or -Br.
5.5.3 Methods for Making Compounds of Formula I where W is N and the
Dashed Line is Absent
The compounds of formula I where W is N and the dashed line is absent, i.e.,
"Piperazine Compounds," can be made using conventional organic synthesis or by
the
following illustrative methods shown in the schemes below.
5.5.3.1 Methods for Making Piperazine Compounds where X is 0 and Arlil
a Benzothiazolyl Group
Piperazine Compounds where X is 0, Ar2 is a benzothiazolyl group, and R20 is
-H, can be obtained by the following illustrative method shown in scheme 3,1:
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Scheme 3.1
An
NO2
ale
Ari
HN 0
R20,N ___________________________________________________________
(R )rn SN
N) 3
43
R9
R8 R8
44 R9
Piperazine Compounds
where An, R3, R8, R9 and m are as defined above.
A compound of formula 44 (about 2mmol) is dissolved in an aprotic organic
solvent (about 3mL). To the resulting solution is added a compound of formula
43
(about 2mmol) and the reaction mixture allowed to stir for about 10 min. The
reaction
mixture is concentrated under reduced pressure to provide the Piperazine
Compounds
where X is 0, Ar2 is a benzothiazolyl group, and 1Z20 is -H. Such Piperazine
Compounds
can be chromatographed on a silica column eluted with 5:95 ethyl
acetate:hexane.
The compound of formula 44 can be obtained as shown below in scheme 3.2:
Scheme 3.2
NO2
NH2
0
HN
0
41110
02NN
45 R9 R8
46
R9 44
R8
where R8 and R9 are as defined above.
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A compound of formula 45 (about 0.75mmol) in an aprotic organic solvent
(about 0.04M) is cooled to about 0 C. To the cooled solution is slowly added a
solution
of a compound of formula 46 (about 0.75mmol) in an aprotic organic solvent
(about
0.4M). The reaction mixture is stirred at 0 C for about 5 min. and about
0.75mmol of
triethylamine are added to the reaction mixture. The reaction mixture is then
allowed to
warm to a temperature of about 25 C and concentrated under reduced pressure to
provide the compound of formula 44. The compound of formula 45 is commercially
available, e.g., from Sigma-Aldrich. Compounds of formula 46 are commercially
available or can be prepared by the following illustrative method shown below
in
scheme 3.3:
Scheme 3.3
NH2
NH2 VL
S ' N
4
+ KSCN 0 1. Bromine, Acetic acid ...-
2. NH4OH
411
R9 R8
R9 R8
47 46
where R8 and R9 are as defined above.
To a stirred solution of aniline 47 (about 74mmol) and potassium thiocyanate
(about 148mmol) in about 100mL of glacial acetic acid is added dropwise a
solution of
bromine (about 74mmol) in about 25mL of glacial acetic acid. The flask
containing the
bromine in acetic acid is then rinsed with about 15mL of acetic acid which is
combined
with the solution of aniline 47. The reaction mixture is vigorously stirred at
a
temperature of about 25 C for between about 2 h and about 24 h. The reaction
mixture
is then poured over crushed ice (about 500mL) and the pH of the resulting
mixture
adjusted to a value of about 10 using ammonium hydroxide to provide a
precipitate. The
resulting precipitate is collected by filtration and recrystallized from
toluene to provide
the compound of formula 46. Compounds of formula 47 are commercially available
or
can be prepared by methods known in the art.
The compound of formula 50a-d can be obtained as shown below in scheme 3.4:
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Scheme 3.4
(R2)n
(R2) NThn
___________________________________________________________ Ri N
(R3)m
Ri
(R3)m
48 49a
50a
(R2)p
N\
(R2)p
N\
48
Ri
T¨(R3)rn
49b
50b
(R2)p
(R2)p I I
IR1N
48
FRiN
(R3)m
49c
50c
(R2)p
(R2)p I I
XNRlN
48 I I
(R3)m
49d
50d
where RI, R2, R3, M, n, and p are as defined above and L is a halogen.
A compound of formula 49a-d (about 20mmol) is reacted with a compound of
formula 48 (about 27.5mmol) in about 15mL of DMSO in the presence of
triethylamine
(about 30mmol), optionally with heating, for about 24 h to provide a compound
of
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formula 50a-d. The compound of formula 50a-d is isolated from the reaction
mixture
and further treated if desired. In one embodiment, the compound of formula 50a-
d is
chromatographed using column chromatography or recrystallized.
Compounds of formula 48 and 49a-d are commercially available or can be
prepared by methods known in the art. The compound of formula 48 where m is 0
and
the compound of formula 48 where rn is 1 and R3 is (R) -CH3 or (S) -CH3 are
commercially available, e.g., from Sigma-Aldrich. In one embodiment, L is
bromide,
chloride, or iodide.
Piperazine Compounds where X is 0, Ai-) is a benzothiazolyl group, and R10 is
-(C1-C4)alkyl can be obtained by the following illustrative method shown below
in
scheme 3.5:
Scheme 3.5
Ari
Ari
N,
¨1 (R36
N7 7(R3)rn
HN NaH
20N
SAN R70-L
SAN
=
R8
R9 R8
R9
where Ark R3, R8, R9, R20, and m are as defined above and L is a halogen.
To a solution of a Piperazine Compound where X is 0, Ar2 is a benzothiazolyl
group, and R20 is -H (about leq.), obtained as described above in Scheme 3.1,
in DMF at
0 C, is added a DMF solution of NaH (about 2 eq.). The reaction mixture is
allowed to
warm to a temperature of about 25 C over about 1 h. To the resulting mixture
is added
about 1.2eq. of an alkyl halide, R20-L, and the reaction mixture allowed to
stir until the
Piperazine Compounds where X is 0, Ar) is a benzothiazolyl group, and R20 is -
(Ci-
C4)alkyl form. The progress of the reaction can be monitored using
conventional
analytical techniques including, but not limited to, high pressure liquid
chromatography
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(HPLC), column chromatography, thin-layer chromatography (TLC), column
chromatography, gas chromatography, mass spectrometry, and nuclear magnetic
resonance spectroscopy such as 1H and 13C NMR. Piperazine Compounds can be
isolated and further treated if desired. In one embodiment, the Piperazine
Compound is
isolated by removing the solvent under reduced pressure. In another
embodiment, the
Piperazine Compound is isolated by extraction. Piperazine Compounds can be
further
treated, for example, by column chromatography or recrystallization.
5.5.3.2 Methods for Making Piperazine Compounds where X is S and Ar2 is
a Benzothiazolyl Group
Piperazine Compounds where X is S, Ar2 is a benzothiazolyl group, and R20 is -
H can be obtained by the following illustrative method in scheme 3.6.
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Scheme 3.6
NH2
N1
N 7
1\1[
N HN N
I
DMAP
DMSO 100 C S4N
R9
111
R8
46 R9
R8
Ar1
j(R3)rn DMSO 100 C
43
An
(R3)m
HN __ S
SN
11110
R8
R9
Piperazine Compounds
where Ari, R3, Rg, R, and m are as defined above.
A compound of formula 46 (about 2mmol), 1,1'-thiocarbonyldiimidazole (about
2mmol) (Sigma-Aldrich), and 4-dimethylaminopyridine (DMAP) (Sigma-Aldrich) are
suspended in DMSO (about 3mL) at a temperature of about 25 C and the resulting
mixture is heated at about 100 C for about 6 h. The reaction mixture is then
cooled to a
temperature of about 25 C and a compound of formula 43 (about 2mmol) is added
to the
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reaction mixture and the reaction mixture is heated to about 100 C for about
16 h. The
reaction mixture is concentrated under reduced pressure to provide Piperazine
Compounds where X is S, Ar2 is a benzothiazolyl group, and R20 is -H.
Piperazine
Compounds can be chromatographed on a silica column eluted with 5:95 ethyl
acetate:hexane.
Piperazine Compounds where X is S, Ar2 is a benzothiazolyl group, and R20 is
-(C1-C4)alkyl can be obtained by a method analogous to the method used to
obtain
Piperazine Compounds where X is 0, Ar2 is a benzothiazolyl group, and R?c, is -
(Ci-
C4)alkyl as described above in Scheme 3.5 except that a Piperazine Compound
where X
is S, Ar2 is a benzothiazolyl group, and R70 is -H, obtained as described
above in
Scheme 3.6, is used in place of the Piperazine Compound where X is 0, Ar2 is a
benzothiazolyl group, and R20 is -H.
5.5.3.3 Methods for Making Piperazine Compounds Where X is 0 and Ar2
is a Benzooxazolyi Group
Piperazine Compounds where X is 0, Ar2 is a benzooxazolyl group, and R20 is
-H can be obtained by a method analogous to that used to obtain the Piperazine
Compounds where X is 0, Ar2 is a benzothiazolyl, and R20 is -H as described in
section
5.4.3.1, scheme 3.1, except that a compound of formula 51, shown below:
NO2
0
=
HNO
04N
1110
R9
R8
51
where R8 and R9 are as defined above, is used in place of the compound of
formula 44.
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The compound of formula 51 can be obtained by a method analogous to that
used to obtain the compound of formula 44 as described above in Scheme 3.2
except
that a compound of formula 52, shown below,
NH2
CAN
R9
R8
52
where R8 and R9 are as defined above, is used in place of compound 46.
5.5.3.4 Methods for Making Piperazine Compounds Where X is S and Ar2 is
a Benzooxazolyi Group
Piperazine Compounds where X is S, Ar2 is a benzooxazolyl group, and RN) is -H
can be obtained by a method analogous to that used to obtain the Piperazine
Compounds
described above in Scheme 3.6 except that a compound of formula 53 is used in
place of
the compound of formula 44. The compound of Formula 53 can be obtained as
described above.
NO2
=
HN 0
ON
R9
53
Piperazine Compounds where X is S, Ar2 is a benzooxazolyl group, and R20 is
-(Ci-C4)alkyl can be obtained by a method analogous to the method used to
obtain the
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Piperazine Compounds described above in Scheme 3.5 except that a Piperazine
Compound where X is S, Ar2 is a benzooxazolyl group, and R20 is -H, obtained
as
described above, is used in place of the Piperazine Compound where X is 0, Ai-
) is a
benzothiazolyl group, and R70 is -H.
5.5.3.5 Methods for Making Piperazine Compounds Where X is 0 and Ar2
is a Benzoimidiazolyl Group
Piperazine Compounds where X is 0, Ar2 is a benzoimidiazolyl group, the amide
R20 is -H, and the benzoimidiazolyl group R20 is -H can be obtained by a
method
analogous to that used to obtain the Piperazine Compounds described above in
Scheme
3.1 except that a compound of formula 54, shown below,
NO2
HN 0
HN4N
R9 R8
54
where R8 and R9 are as defined above, is used in place of the compound of
formula 44.
The Compound of formula 54 can be obtained by a method analogous to that
used to obtain the compound of formula 44 as described in section 5.4.3.1,
Scheme 3.2,
except that a compound of formula 55, shown below,
NH2
HN4N
1110
R9 R8
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where R8 and R9 are as defined above, is used in place of the compound of
formula 46.
Compounds of formula 55 are commercially available or can be prepared by
procedures
known in the art. An illustrative procedure for obtaining compound 55 is shown
below
in Scheme 3.7:
Scheme 3.7
R8 =R9 Si N R8 40 N
-NH2
CI Aqueous NH3
R9
56 55
where R8 and R9 are as defined above.
A compound of formula 56 (about lmmol), prepared as described below in
Scheme 3.11, is dissolved in excess aqueous ammonia in a sealed tube and
heated at a
temperature of between about 140 C and 150 C for about 72 h. The mixture is
cooled to
a temperature of about 25 C and concentrated under reduced pressure to provide
a
residue. In another embodiment, the mixture is cooled to a temperature of
about 25 C,
extracted with an organic solvent, the organic phase separated from the
aqueous phase,
and the organic phase is concentrated under reduced pressure to provide a
residue. If
desired, the residue is then further treated to provide the compound of
formula 55. In
one embodiment, the residue is recrystallized. In another embodiment, the
residue is
chromatographed using flash chromatography.
Compounds of formula 56 are commercially available or can be prepared by
procedures known in the art. An illustrative method for preparing the compound
of
formula 56 is shown below in scheme 3.8:
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Scheme 3.8
R8 is NH2
CDI R8 N> __ 0
Rg NH2 Rg
57 58
POCI3
R8 I. N
R9
56
where R8 and R9 are as defined above.
A compound of formula 57 (about 5 mmol to about lOmmol) and di(1H-
imidazol-1-yl)methanone (CDI, about 2 eq) is dissolved in THF (about 50mL to
about
70mL) and the reaction mixture is heated at reflux temperature for about 4
hours. The
reaction mixture is then concentrated under reduced pressure to provide a
residue. Ethyl
acetate (about 50mL) is added to the residue and the resulting insoluble
material is
collected by filtration and washed with ethyl acetate to provide a compound of
formula
58. The compound of formula 58 is then reacted with POC13 according to the
procedure
described in J. Med. Chem. 40:586-593 (1997) to provide the compound of
formula 56.
The compounds of formula 57 are commercially available or can be prepared by
procedures known in the art. An illustrative procedure for obtaining a
compound of
formula 57 is shown below in scheme 3.9:
Scheme 3.9
R8 401 NH2 H2SO4 R8 40 NH2 H, R8 40 NH2
Rg = HCI FIN03 R9
NO2 10% Pd/C Rg NH2
59 60 57
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where R8 and R9 are as defined above.
Aniline hydrochloride 59 (about 12mmol) is dissolved in concentrated sulfuric
acid (about 10mL) at 0 C and the resulting solution cooled to a temperature of
about
-13 C to about -15 C. About lmL of 70% nitric acid is added to the resulting
solution
over a time period of about 30 min. and the reaction mixture allowed to stir
for about 2 h
at a temperature of from about -13 C to about -15 C. The reaction mixture is
then
poured into ice water (about 100mL), neutralized with 5% to 10% aqueous sodium
hydroxide, and extracted with about 50mL of chloroform. The chloroform layer
is
separated from the aqueous layer. Concentration under reduced pressure
provides a
residue that is chromatographed using flash chromatography (silica column and
chloroform eluent) to provide a compound of formula 60. The compound of
formula 60
is dissolved in ethanol (about 50mL) and hydrogenated for about 12 h at a
temperature
of about 25 C using 10% palladium on carbon as a catalyst. The catalyst is
removed by
filtration and the ethanol is removed under reduced pressure to provide a
residue that is
chromatographed using flash chromatography (silica gel eluted with 20:1
dichloromethane:methanol) to provide the compound of formula 57. The compounds
of
formula 59 are commercially available or can be prepared by procedures known
in the
art.
Piperazine Compounds where X is 0, Ai-) is a benzoimidiazolyl group, the amide
R70 is -H, and the benzoimidiazolyl group R/0 is -(Ci-C4)alkyl can be obtained
by a
method analogous to that used to obtain the Piperazine Compounds where X is 0,
Ar2 is
a benzoimidiazolyl group, the amide R20 is -H, and the benzoimidiazolyl group
R20 is -H
except that a compound of formula 61, shown below,
NO2
0
HN)1-13
R2o
N4N
R9 R8
61
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where Rg, R9, and R20 are as defined above, is used in place of the compound
of formula
54. The compound of formula 61 can be obtained by a method analogous to that
used to
obtain the compound of formula 54 except that a compound of formula 62, shown
below,
NH2
R20
N
R9
R8
62
where R8, R9, and R20 are as defined above, is used in place of the compound
of formula
55. The compound of formula 62 can be obtained as shown below in scheme 3.10.
Scheme 3.10
NH2 NH2 NHR20
HN4NNaH R20 N4N HN4N
1110
DMF
=
R,0-L
R9 R9 R9
R8 R8 R8
55 62 63
where Rg, R9, and R20 are as defined above and L is a halogen.
NaH (about 2 eq) is added to a solution of a compound of formula 55 in DMF at
0 C and the resulting mixture is allowed to stir and to warm to a temperature
of about
C over a period of about one hour. An alkyl halide, R20-L, (about leq.) is
then added
to the solution and the reaction mixture allowed to stir until a mixture of a
compound of
20 formula 62 and a compound of formula 63 is produced. In one embodiment,
the alkyl
halide is an alkyl iodide. The formation of the compound of formula 62 and the
compound of formula 63 can be monitored by analytical methods known in the art
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including, but not limited to, those described above. Water is then added to
the reaction
mixture to produce a precipitate of the compound of formula 62 and the
compound of
formula 63, which are collected by filtration. The compound of formula 62 and
the
compound of formula 63 are then separated to provide the compound of formula
62.
The compound of formula 62 and the compound of formula 63 can be separated by
methods known in the art including, but not limited to, column chromatography,
preparative TLC, preparative HPLC, and preparative GC.
5.5.3.6 Methods for Making Piperazine Compounds Where X is S and Ar2 is
a Benzoimidiazolyl Group
Piperazine Compounds where X is S, Ai-, is a benzoimidiazolyl group, the
thioamide R20 is -H, and the benzoimidiazolyl group R20 is -H can be obtained
by a
method analogous to that used to obtain the Piperazine Compounds described
above in
scheme 3.6 except that a compound of formula 55 is used in place of the
compound of
formula 46. The compound of formula 55 can be obtained as described above.
Piperazine Compounds where X is S, Ar, is a benzoimidiazolyl group, the
thioamide R20 is -H, and the benzoimidiazolyl group 1Z20 is -(Ci-C4)alkyl can
be obtained
by a method analogous to that used to obtain Piperazine Compounds as described
in
section 5.4.3.2, scheme 3.6, except that a compound of formula 62 is used in
place of the
compound of formula 46. The compound of formula 62 can be obtained as
described
above.
Piperazine Compounds where X is S, Au2 is a benzoimidiazolyl group, the
thioamide R20 is -(Ci-C4)alkyl, and the benzoimidiazolyl group R20 is -H can
be obtained
by a method analogous to that used to obtain the Piperazine Compounds as
described
above in scheme 3.5 except that a Piperazine Compound where X is S and each
R20 is
prepared as described above, is used in place of the Piperazine Compounds
where X
is 0 and the amide R20 is -H.
Piperazine Compounds where X is S, Ar) is a benzoimidiazolyl group, the
thioamide R70 is -(C1-C4)alkyl, and the benzoimidiazolyl group R70 is -(Ci-
C4)alkyl can
be obtained by a method analogous to that used to obtain the Piperazine
Compounds
where X is 0 and RN) is -(Ci-C4)alkyl as described above in scheme 3.5 except
that the
Piperazine Compound where X is S, the thioamide lt20 is -H, and the
benzoimidiazolyl
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group R20 is -(C1-C4)alkyl, prepared as described above, is used in place of
the
Piperazine Compound where X is 0 and R20 is -H.
Suitable aprotic organic solvents for use in the illustrative methods include,
but
are not limited to, DCM, DMSO, chloroform, toluene, benzene, acetonitrile,
carbon
tetrachloride, pentane, hexane, ligroin, and diethyl ether. In one embodiment,
the
aprotic organic solvent is DCM.
Certain Piperazine Compounds can have one or more asymmetric centers and
therefore exist in different enantiomeric and diastereomeric forms. A
Piperazine
Compound can be in the form of an optical isomer or a diastereomer.
Accordingly, the
invention encompasses Piperazine Compounds and their uses as described herein
in the
form' of their optical isomers, diastereomers, and mixtures thereof, including
a racemic
mixture.
In addition, one or more hydrogen, carbon or other atoms of a Piperazine
Compound can be replaced by an isotope of the hydrogen, carbon or other atoms.
Such
compounds, which are encompassed by the invention, are useful as research and
diagnostic tools in metabolism pharmacokinetic studies and in binding assays.
5.6 THERAPEUTIC USES OF COMPOUNDS OF FORMULA I
In accordance with the invention, the compounds of formula I are administered
to an animal in need of treatment or prevention of a Condition.
In one embodiment, an effective amount of a compound of formula I can be used
to treat or prevent any condition treatable or preventable by inhibiting TRPV
I .
Examples of Conditions that are treatable or preventable by inhibiting TRPV1
include,
but are not limited to, pain, UI, an ulcer, IBD, and IBS.
The compounds of formula I, or a pharmaceutically acceptable derivative
thereof, can be used to treat or prevent acute or chronic pain. Examples of
pain treatable
or preventable using the compounds of formula I include, but are not limited
to, cancer
pain, labor pain, myocardial infarction pain, pancreatic pain, colic pain,
post-operative
pain, headache pain, muscle pain, arthritic pain, and pain associated with a
periodontal
disease, including gingivitis and periodontitis.
The compounds of formula I, or a pharmaceutically acceptable derivative
thereof, can also be used for treating or preventing pain associated with
inflammation or
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with an inflammatory disease in an animal. Such pain can arise where there is
an
inflammation of the body tissue which can be a local inflammatory response
and/or a
systemic inflammation. For example, the compounds of formula I can be used to
treat
or prevent pain associated with inflammatory diseases including, but not
limited to:
organ transplant rejection; reoxygenation injury resulting from organ
transplantation (see
Grupp et al., J. Mol. Cell Cardiol. 31:297-303 (1999)) including, but not
limited to,
transplantation of the heart, lung, liver, or kidney; chronic inflammatory
diseases of the
joints, including arthritis, rheumatoid arthritis, osteoarthritis and bone
diseases
associated with increased bone resorption; inflammatory bowel diseases, such
as ileitis,
ulcerative colitis, Barrett's syndrome, and Crohn's disease; inflammatory lung
diseases,
such as asthma, adult respiratory distress syndrome, and chronic obstructive
airway
disease; inflammatory diseases of the eye, including corneal dystrophy,
trachoma,
onchocerciasis, uveitis, sympathetic ophthalmitis and endophthalmitis; chronic
inflammatory diseases of the gum, including gingivitis and periodontitis;
tuberculosis;
leprosy; inflammatory diseases of the kidney, including uremic complications,
glomerulonephritis and nephrosis; inflammatory diseases of the skin, including
sclerodermatitis, psoriasis and eczema; inflammatory diseases of the central
nervous
system, including chronic demyelinating diseases of the nervous system,
multiple
sclerosis, AIDS-related neurodegeneration and Alzheimer s disease, infectious
meningitis, encephalomyelitis, Parkinson's disease, Huntington's disease,
amyotrophic
lateral sclerosis and viral or autoimmune encephalitis; autoimmune diseases,
including
Type I and Type II diabetes mellitus; diabetic complications, including, but
not limited
to, diabetic cataract, glaucoma, retinopathy, nephropathy (such as
microaluminuria and
progressive diabetic nephropathy), polyneuropathy, mononeuropathies, autonomic
neuropathy, gangrene of the feet, atherosclerotic coronary arterial disease,
peripheral
arterial disease, nonketotic hyperglycemic-hyperosmolar coma, foot ulcers,
joint
problems, and a skin or mucous membrane complication (such as an infection, a
shin
spot, a candidal infection or necrobiosis lipoidica diabeticorum); immune-
complex
vasculitis, and systemic lupus erythematosus (SLE); inflammatory diseases of
the heart,
such as cardiomyopathy, ischemic heart disease hypercholesterolemia, and
atherosclerosis; as well as various other diseases that can have significant
inflammatory
components, including preeclampsia, chronic liver failure, brain and spinal
cord trauma,
and cancer. The compounds of formula I can also be used for inhibiting,
treating, or
preventing pain associated with inflammatory disease that can, for example, be
a
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systemic inflammation of the body, exemplified by gram-positive or gram
negative
shock, hemorrhagic or anaphylactic shock, or shock induced by cancer
chemotherapy in
response to pro-inflammatory cytokines, e.g., shock associated with pro-
inflammatory
cytokines. Such shock can be induced, e.g., by a chemotherapeutic agent that
is
adminstered as a treatment for cancer.
The compounds of formula I, or a pharmaceutically acceptable derivative
thereof, can be used to treat or prevent Ul. Examples of UI treatable or
preventable
using the compounds of formula I include, but are not limited to, urge
incontinence,
stress incontinence, overflow incontinence, neurogenic incontinence, and total
incontinence.
The compounds of formula I, or a pharmaceutically acceptable derivative
thereof, can be used to treat or prevent an ulcer. Examples of ulcers
treatable or
preventable using the compounds of formula I include, but are not limited to,
a duodenal
ulcer, a gastric ulcer, a marginal ulcer, an esophageal ulcer, or a stress
ulcer.
The compounds of formula I, or a pharmaceutically acceptable derivative
thereof, can be used to treat or prevent IBD, including Crohn's disease and
ulcerative
colitis.
The compounds of formula I, or a pharmaceutically acceptable derivative
thereof, can be used to treat or prevent IBS. Examples of IBS treatable or
preventable
using the compounds of formula I include, but are not limited to, spastic-
colon-type IBS
and constipation-predominant IBS.
Applicants believe that the compounds of formula I, or a pharmaceutically
acceptable derivative thereof, are antagonists for TRPV1. The invention also
relates to
methods for inhibiting TRPV1 function in a cell comprising contacting a cell
capable of
expressing TRPV I with an effective amount of a compound of formula I, or a
pharmaceutically acceptable derivative thereof. This method can be used in
vitro, for
example, as an assay to select cells that express TRPV1 and, accordingly, are
useful as
part of an assay to select compounds useful for treating or preventing pain,
Ul, an ulcer,
IBD, or IBS. The method is also useful for inhibiting TRPV1 function in a cell
in vivo,
in an animal, a human in one embodiment, by contacting a cell, in an animal,
with an
effective amount of a compound of formula I, or a pharmaceutically acceptable
derivative thereof. In one embodiment, the method is useful for treating or
preventing
pain in an animal. In another embodiment, the method is useful for treating or
preventing Ul in an animal. In another embodiment, the method is useful for
treating or
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preventing an ulcer in an animal. In another embodiment, the method is useful
for
treating or preventing IBD in an animal. In another embodiment, the method is
useful
for treating or preventing IBS in an animal.
Examples of tissue comprising cells capable of expressing TRPV1 include, but
are not limited to, neuronal, brain, kidney, urothelium, and bladder tissue.
Methods for
assaying cells that express TRPV I are known in the art.
5.7 THERAPEUTIC/PROPHYLACTIC ADMINISTRATION AND
COMPOSITIONS OF THE INVENTION
Due to their activity, compounds of formula I, or a pharmaceutically
acceptable
derivative thereof, are advantageously useful in veterinary and human
medicine. As
described above, compounds of formula I, or a pharmaceutically acceptable
derivative
thereof, are useful for treating or preventing a Condition.
When administered to an animal, compounds of formula I, or a pharmaceutically
acceptable derivative thereof, are typically administered as a component of a
composition that comprises a pharmaceutically acceptable carrier or excipient.
The
present compositions, which comprise a compound of formula I, or a
pharmaceutically
acceptable derivative thereof, can be administered orally. Compounds of
formula I, or a
pharmaceutically acceptable derivative thereof, can also be administered by
any other
convenient route, for example, by infusion or bolus injection, by absorption
through
epithelial or mucocutaneous linings (e.g., oral, rectal, and intestinal
mucosa, etc.) and
can be administered together with another therapeutically active agent.
Administration
can be systemic or local. Various delivery systems are known, e.g.,
encapsulation in
liposomes, microparticles, microcapsules, capsules, etc., and can be used to
administer
the compound of formula I, or a pharmaceutically acceptable derivative
thereof.
Methods of administration include, but are not limited to, intradermal,
intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal,
epidural, oral,
sublingual, intracerebral, intravaginal, transdermal, rectal, by inhalation,
or topical,
particularly to the ears, nose, eyes, or skin. The mode of administration is
left to the
discretion of the practitioner. In most instances, administration will result
in the release
of compounds of formula 1, or a pharmaceutically acceptable derivative
thereof, into the
bloodstream.
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In specific embodiments, it can be desirable to administer the compounds of
formula I, or a pharmaceutically acceptable derivative thereof, locally. This
can be
achieved, for example, and not by way of limitation, by local infusion during
surgery,
topical application, e.g., in conjunction with a wound dressing after surgery,
by
injection, by means of a catheter, by means of a suppository or enema, or by
means of an
implant, said implant being of a porous, non-porous, or gelatinous material,
including
membranes, such as sialastic membranes, or fibers.
In certain embodiments, it can be desirable to introduce the compounds of
formula I, or a pharmaceutically acceptable derivative thereof, into the
central nervous
system or gastrointestinal tract by any suitable route, including
intraventricular,
intrathecal, and epidural injection, and enema. Intraventricular injection can
be
facilitated by an intraventricular catheter, for example, attached to a
reservoir, such as an
Ommaya reservoir.
Pulmonary administration can also be employed, e.g., by use of an inhaler or
nebulizer, and formulation with an aerosolizing agent, or via perfusion in a
fluorocarbon
or synthetic pulmonary surfactant. In certain embodiments, the compounds of
formula I
can be formulated as a suppository, with traditional binders and excipients
such as
triglycerides.
In another embodiment, the compounds of formula I, or a pharmaceutically
acceptable derivative thereof, can be delivered in a vesicle, in particular a
liposome (see
Langer, Science 249:1527-1533 (1990) and Treat eta!,, Liposomes in the Therapy
of
Infectious Disease and Cancer 317-327 and 353-365 (1989)).
In yet another embodiment, the compounds of fonnula I, or a pharmaceutically
acceptable derivative thereof, can be delivered in a controlled-release system
or
sustained-release system (see, e.g., Goodson, in Medical Applications of
Controlled
Release, supra, vol. 2, pp. 115-138 (1984)). Other controlled- or sustained-
release
systems discussed in the review by Langer, Science 249:1527-1533 (1990) can be
used.
In one embodiment, a pump can be used (Langer, Science 249:1527-1533 (1990);
Sefton, CRC Crit. Rgf. Biomed. Eng. 14:201 (1987); Buchwald etal., Surgery
88:507
(1980); and Saudek etal., IV. Engl. J. Med. 321:574 (1989)). In another
embodiment,
polymeric materials can be used (see Medical Applications of Controlled
Release
(Langer andWise eds., 1974); Controlled Drug Bioavailability, Drug Product
Design
and Performance (Smolen and Ball eds., 1984); Ranger and Peppas, J. Macromol.
Sci.
Rev. Macromol. Chem. 23:61 (1983); Levy etal., Science 228:190 (1985); During
etal.,
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Ann. Neurol. 25:351 (1989); and Howard et al., J. Neurosurg. 71:105 (1989)).
In yet
another embodiment, a controlled- or sustained-release system can be placed in
proximity of a target of the compounds of formula I, e.g., the spinal column,
brain, or
gastrointestinal tract, thus requiring only a fraction of the systemic dose.
The present compositions can optionally comprise a suitable amount of a
pharmaceutically acceptable excipient so as to provide the form for proper
administration to the animal.
Such pharmaceutical excipients can be liquids, such as water and oils,
including
those of petroleum, animal, vegetable, or synthetic origin, such as peanut
oil, soybean
oil, mineral oil, sesame oil and the like. The pharmaceutical excipients can
be saline,
gum acacia, gelatin, starch paste, talc, keratin, colloidal silica, urea and
the like. In
addition, auxiliary, stabilizing, thickening, lubricating, and coloring agents
can be used.
In one embodiment, the pharmaceutically acceptable excipients are sterile when
administered to an animal. Water is a particularly useful excipient when the
compound
of formula! is administered intravenously. Saline solutions and aqueous
dextrose and
glycerol solutions can also be employed as liquid excipients, particularly for
injectable
solutions. Suitable pharmaceutical excipients also include starch, glucose,
lactose,
sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate,
glycerol
monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene,
glycol, water,
ethanol and the like. The present compositions, if desired, can also contain
minor
amounts of wetting or emulsifying agents, or can contain pH buffering agents.
The present compositions can take the form of solutions, suspensions,
emulsion,
tablets, pills, pellets, multiparticulates, capsules, capsules containing
liquids, powders,
multiparticulates, sustained-release formulations, suppositories, emulsions,
aerosols,
sprays, suspensions, or any other form suitable for use. In one embodiment,
the
composition is in the form of a capsule (see e.g., U.S. Patent No. 5,698,155).
Other
examples of suitable pharmaceutical excipients are described in Remington 's
Pharmaceutical Sciences 1447-1676 (Alfonso R. Gennaro ed., 19th ed. 1995).
In one embodiment, the compounds of formula I, or a pharmaceutically
acceptable derivative thereof, are formulated in accordance with routine
procedures as a
composition adapted for oral administration to human beings. Compositions for
oral
delivery can be in the form of tablets, lozenges, aqueous or oily suspensions,
granules,
powders, emulsions, capsules, syrups, or elixirs, for example. Orally
administered
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compositions can contain one or more agents, for example, sweetening agents
such as
fructose, aspartame or saccharin; flavoring agents such as peppermint, oil or
wintergreen, or cherry; coloring agents; and preserving agents, to provide a
pharmaceutically palatable preparation. Moreover, where in tablet or pill
form, the
compositions can be coated to delay disintegration and absorption in the
gastrointestinal
tract thereby providing a sustained action over an extended period of time.
Selectively
permeable membranes surrounding an osmotically active driving compound are
also
suitable for orally administered compositions. In these latter platforms,
fluid from the
environment surrounding the capsule is imbibed by the driving compound, which
swells
to displace the agent or agent composition through an aperture. These delivery
platforms can provide an essentially zero order delivery profile as opposed to
the spiked
profiles of immediate release formulations. A time-delay material such as
glycerol
monostearate or glycerol stearate can also be used. Oral compositions can
include
standard excipients such as maimitol, lactose, starch, magnesium stearate,
sodium
saccharin, cellulose, and magnesium carbonate. In one embodiment, the
excipients are
of pharmaceutical grade.
The compounds of formula 1, or a pharmaceutically acceptable derivative
thereof, can be administered by controlled-release or sustained-release means
or by
delivery devices that are known to those of ordinary skill in the art.
Examples include,
but are not limited to, those described in U.S. Patent Nos.: 3,845,770;
3,916,899;
3,536,809; 3,598,123; 4,008,719; 5,674,533; 5,059,595; 5,591,767; 5,120,548;
5,073,543; 5,639,476; 5,354,556; and 5,733,566..
Such dosage forms can be used to provide controlled- or sustained-release of
one or more active ingredients using, for example, hydropropylmethyl
cellulose,
ethylcellulose, other polymer matrices, gels, permeable membranes, osmotic
systems,
multilayer coatings, microparticles, liposomes, microspheres, or a combination
thereof
to provide the desired release profile in varying proportions. Suitable
controlled- or
sustained-release formulations known to those of ordinary skill in the art,
including
those described herein, can be readily selected for use with the active
ingredients of the
invention. The invention thus encompasses single unit dosage forms suitable
for oral
administration such as, but not limited to, tablets, capsules, gel caps, and
caplets that are
adapted for controlled- or sustained-release.
Controlled- or sustained-release pharmaceutical compositions can have a
common goal of improving drug therapy over that achieved by their non-
controlled or
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non-sustained release counterparts. In one embodiment, a controlled- or
sustained-
release composition comprises a minimal amount of a compound of formula Ito
cure or
control the condition in a minimum amount of time. Advantages of controlled-
or
sustained-release compositions include extended activity of the drug, reduced
dosage
frequency, and increased patient compliance. In addition, controlled- or
sustained-
release compositions can favorably affect the time of onset of action or other
characteristics, such as blood levels of the compound of formula I, and can
thus reduce
the occurrence of adverse side effects.
Controlled- or sustained-release compositions can be designed to immediately
release an amount of a compound of formula I, or a pharmaceutically acceptable
derivative thereof, that promptly produces the desired therapeutic or
prophylactic effect,
and gradually and continually release other amounts of the compound of formula
Ito
maintain this level of therapeutic or prophylactic effect over an extended
period of time.
To maintain a constant level of the compound of formula! in the body, the
compound of
formula I can be released from the dosage form at a rate that will replace the
amount of
compound of formula I being metabolized and excreted from the body. Controlled-
or
sustained-release of an active ingredient can be stimulated by various
conditions,
including but not limited to, changes in pH, changes in temperature,
concentration or
availability of enzymes, concentration or availability of water, or other
physiological
conditions or compounds.
In another embodiment, the compounds of formula I, or a pharmaceutically
acceptable derivative thereof, can be formulated for intravenous
administration.
Typically, compositions for intravenous administration comprise sterile
isotonic aqueous
buffer. Where necessary, the compositions can also include a solubilizing
agent.
Compositions for intravenous administration can optionally include a local
anaesthetic
such as lignocaine to lessen pain at the site of the injection. Generally, the
ingredients
are supplied either separately or mixed together in unit dosage form, for
example, as a
dry lyophilized powder or water free concentrate in a hermetically sealed
container such
as an ampoule or sachette indicating the quantity of active agent. Where the
compounds
of formula I are to be administered by infusion, they can be dispensed, for
example, with
an infusion bottle containing sterile pharmaceutical grade water or saline.
Where the
compounds of formula I, or a pharmaceutically acceptable derivative thereof,
are
administered by injection, an ampoule of sterile water for injection or saline
can be
provided so that the ingredients can be mixed prior to administration.
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The amount of the compound of formula I, or a pharmaceutically acceptable
derivative thereof, that is effective in the treatment or prevention of a
Condition can be
determined by standard clinical techniques. In addition, in vitro or in vivo
assays can
optionally be employed to help identify optimal dosage ranges. The precise
dose to be
employed will also depend on the route of administration, and the seriousness
of the
Condition and can be decided according to the judgment of a practitioner
and/or each
animal's circumstances. Suitable effective dosage amounts, however, will
typically
range from about 0.01 mg/kg of body weight to about 2500 mg/kg of body weight,
although they are typically about 100 mg/kg of body weight or less. In one
embodiment, the effective dosage amount ranges from about 0.01 mg/kg of body
weight
to about 100 mg/kg of body weight of a compound of formula I; in another
embodiment,
about 0.02 mg/kg of body weight to about 50 mg/kg of body weight; and in
another
embodiment, about 0.025 mg/kg of body weight to about 20 mg/kg of body weight.
In one embodiment, an effective dosage amount is administered about every 24 h
until the Condition is abated. In another embodiment, an effective dosage
amount is
administered about every 12 h until the Condition is abated. In another
embodiment, an
effective dosage amount is administered about every 8 h until the Condition is
abated.
In another embodiment, an effective dosage amount is administered about every
6 h
until the Condition is abated. In another embodiment, an effective dosage
amount is
administered about every 4h until the Condition is abated.
The effective dosage amounts described herein refer to total amounts
administered; that is, if more than one compound of formula I, or a
pharmaceutically
acceptable derivative thereof, is administered, the effective dosage amounts
correspond
to the total amount administered.
Where a cell capable of expressing TRPV1 is contacted with a compound of
formula I in vitro, the amount effective for inhibiting the TRPV1 receptor
function in a
cell will typically range from about 0.01 tig/L to about 5 mg/L; in one
embodiment,
from about 0.01iug/L to about 2.5 mg/L; in another embodiment, from about 0.01
pg/L
to about 0.5 mg/L; and in another embodiment, from about 0.01 tig/L to about
0.25
mg/L, of a solution or suspension of a pharmaceutically acceptable carrier or
excipient.
In one embodiment, the volume of solution or suspension comprising the
compound of
formula I, or a pharmaceutically acceptable derivative thereof, is from about
0.01 pl to
about lmL. In another embodiment, the volume of solution or suspension is
about 200
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246
The compounds of formula I, or a pharmaceutically acceptable derivative
thereof, can be assayed in vitro or in vivo for the desired therapeutic or
prophylactic
activity prior to use in humans. Animal model systems can be used to
demonstrate
safety and efficacy.
The present methods for treating or preventing a Condition in an animal in
need
thereof can further comprise administering to the animal being administered a
compound
of formula I, or a pharmaceutically acceptable derivative thereof, another
therapeutic
agent. In one embodiment, the other therapeutic agent is administered in an
effective
amount.
The present methods for inhibiting TRPV1 function in a cell capable of
expressing TRPV1 can further comprise contacting the cell with an effective
amount of
another therapeutic agent.
Effective amounts of the other therapeutic agents are known in the art.
However,
it is within the skilled artisan's purview to determine the other therapeutic
agent's
optimal effective-amount range. In one embodiment of the invention, where
another
therapeutic agent is administered to an animal, the effective amount of the
compound of
formula I is less than its effective amount would be where the other
therapeutic agent is
not administered. In this case, without being bound by theory, it is believed
that the
compounds of formula I and the other therapeutic agent act synergistically to
treat or
prevent a Condition.
The other therapeutic agent can be, but is not limited to, an opioid agonist,
a non-
opioid analgesic, a non-steroid anti-inflammatory agent, an antimigraine
agent, a Cox-II
inhibitor, an antiemetic, a I3-adrenergic blocker, an anticonvulsant, an
antidepressant, a
Ca2+-channel blocker, an anticancer agent, an agent for treating or preventing
UI, an
agent for treating or preventing an ulcer, an agent for treating or preventing
IBD, an
agent for treating or preventing IBS, an agent for treating addictive
disorder, an agent for
treating Parkinson's disease and parkinsonism, an agent for treating anxiety,
an agent for
treating epilepsy, an agent for treating a stroke, an agent for treating a
seizure, an agent
for treating a pruritic condition, an agent for treating psychosis, an agent
for treating
Huntington's chorea, an agent for treating ALS, an agent for treating a
cognitive
disorder, an agent for treating a migraine, an agent for treating vomiting, an
agent for
treating dyskinesia, or an agent for treating depression, and mixtures
thereof.
Examples of useful opioid agonists include, but are not limited to,
alfentanil,
allylprodine, alphaprodine, anileridine, benzylmorphine, bezitramide,
buprenorphine,
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247
butorphanol, clonitazene, codeine, desomorphine, dextromoramide, dezocine,
diampromide, diamorphone, dihydrocodeine, dihydromorphine, dimenoxadol,
dimepheptanol, dimethylthiambutene, dioxaphetyl butyrate, dipipanone,
eptazocine,
ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene fentanyl,
heroin,
hydrocodone, hydromorphone, hydroxypethidine, isomethadone, ketobemidone,
levorphanol, levophenacylmorphan, lofentanil, meperidine, meptazinol,
metazocine,
methadone, metopon, morphine, myrophine, nalbuphine, narceine, nicomorphine,
norlevorphanol, normethadone, nalorphine, normorphine, norpipanone, opium,
oxycodone, oxymorphone, papaveretum, pentazocine, phenadoxone, phenomorphan,
phenazocine, phenoperidine, piminodine, piritramide, proheptazine, promedol,
properidine, propiram, propoxyphene, sufentanil, tilidine, tramadol,
pharmaceutically
acceptable derivatives thereof, and mixtures thereof.
In certain embodiments, the opioid agonist is selected from codeine,
hydromorphone, hydrocodone, oxycodone, dihydrocodeine, dihydromorphine,
morphine, tramadol, oxymorphone, pharmaceutically acceptable derivatives
thereof, and
mixtures thereof.
Examples of useful non-opioid analgesics include non-steroidal
anti-inflammatory agents, such as aspirin, ibuprofen, diclofenac, naproxen,
benoxapro fen, flurbipro fen, fenopro fen, flubu fen, ketopro fen, indopro
fen, piropro fen,
carprofen, oxaprozin, pramoprofen, muroprofen, trioxaprofen, suprofen,
aminoprofen,
tiaprofenic acid, fluprofen, bucloxic acid, indomethacin, sulindac, tolmetin,
zomepirac,
tiopinac, zidometacin, acemetacin, fentiazac, clidanac, oxpinac, mefenamic
acid,
meclofenamic acid, flufenamic acid, niflumic acid, tolfenamic acid,
diflurisal, flufenisal,
piroxicam, sudoxicam, isoxicam, and pharmaceutically acceptable derivatives
thereof,
and mixtures thereof. Other suitable non-opioid analgesics include the
following,
non-limiting, chemical classes of analgesic, antipyretic, nonsteroidal anti-
inflammatory
drugs: salicylic acid derivatives, including aspirin, sodium salicylate,
choline
magnesium trisalicylate, salsalate, diflunisal, salicylsalicylic acid,
sulfasalazine, and
olsalazin; para-aminophennol derivatives including acetaminophen and
phenacetin;
indole and indene acetic acids, including indomethacin, sulindac, and
etodolac;
heteroaryl acetic acids, including tolmetin, diclofenac, and ketorolac;
anthranilic acids
(fenamates), including mefenamic acid and meclofenamic acid; enolic acids,
including
oxicams (piroxicam, tenoxicam), and pyrazolidinediones (phenylbutazone,
oxyphenthartazone); and alkanones, including nabumetone. For a more detailed
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248
description of the NSAIDs, see Paul A. Inset, Analgesic-Antipyretic and Anti-
inflammatory Agents and Drugs Employed in the Treatment of Gout, in Goodman &
Gilman 's The Pharmacological Basis qf Therapeutics 617-57 (Perry 13.
Molinhoff and
Raymond W. Ruddon eds., 9' ed. 1996) and Glen R. Hanson, Analgesic.
Antipyretic and
Anti-Inflammatoty Drugs in Remington: The Science and Practice of Pharmacy Vol
II
1196-1221 (A.R. Gennaro ed., 19th ed. 1995),
Examples of useful Cox-11 inhibitors and 5-lipoxygenase inhibitors, as well as
combinations thereof, are described in U.S. Patent No, 6,136,839,
Examples of useful Cox-11 inhibitors include,
but are not limited to, rofecoxib and celecoxib.
Examples of useful antimigraine agents include, but are not limited to,
alpiropride, bromocriptine, dihydroergotamine, dolasctron, ergocomine,
ergocominine,
ergocryptine, ergonovine, ergot, ergotamine, flumedroxone acetate, fonazine,
ketanscrin,
lisuridc, lomcrizine, methylergonovine, methysergide, mctoprolol, naratriptan,
oxetorone, pizotyline, propranotol, risperidone, rizatriptan, sumatriptan,
timolol,
trazodone, zolmitriptan, and mixtures thereof.
The other therapeutic agent can also be an agent useful for reducing any
potential
side effects of a compound of formula 1. For example, the other therapeutic
agent can be
an antiemetic agent. Examples of useful antiemetie agents include, but are not
limited
to, metoclopromide, domperidone, prochlorperazine, promethazine,
chlorpromazine,
trimethobenzamide, ondansetron, granisetron, hydroxyzine, acetylleucine
monoethanolamine, alizapride, azasetron, benzquinamide, bietanautine,
bromopride,
buclizine, clebopride, cyclizine, dimenhydrinate, diphenidol, dolasetron,
meelizine,
methallatal, metopimazine, nabilone, oxyperndyl, pipamazine, scopolamine,
sulpiride,
tetrahydrocannabinol, thiethylperazine, thioproperazine, tropisetron, and
mixtures
thereof.
Examples of useful p-adrenergic blockers include, but are not limited to,
acebutolol, alprenolol, amosulabol, arotinolol, ateriolol, befunolol,
betaxolol, bevantolol,
bisoprolol, bopindolol, bucumo101, bufetolol, bufuralol, bunitrolol,
bupranoloi, butidrine
hydrochloride, butofilolol, carazolol, carteolol, carvedilol, celiprolol,
cetamolol,
cloranolol, dilevalol, epanolol, esmolol, indenolol, labetalol, levobunolol,
mepindolol,
metipranolol, rnetoprolol, moprolol, nadolol, nadoxolol, nebivalol, nifenalol,
nipradilol,
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